Functional neurochemistry of the basal ganglia

Handbook of Clinical Neurology, Vol. 83 (3rd series)Parkinson’s disease and related disorders, Part IW.C. Koller, E. Melamed, Editors# 2007 Elsevier B.V. All rights reserved

Chapter 2

Functional neurochemistry of the basal ganglia

PERSHIA SAMADI 1,2 , CLAUDE ROUILLARD 2, PAUL J. BE DARD 2 AND THE RE SE DI PAOLO 1*

1Centre de Recherche en Endocrinologie Moleculaire et Oncologique, CHUL, Faculte de Pharmacie, and
2Centre de Recherche en Neurosciences, CHUL, Faculte de Medicine,
Universite Laval, Quebec, Canada

Proper execution of voluntary movements results from

the correct processing of feedback loops involving the

cortex, thalamus and basal ganglia (BG). The BG

include a subset of subcortical structures involved in a

variety of processes including motor behavior and also

motor learning and memory process (Graybiel et al.,

1994; Graybiel, 1998; Packard and Knowlton, 2002).

The BG are located in the basal telencephalon and

consist of interconnected structures. The dorsal divisionof the BG is associated with motor and associative func-

tions and consists of the striatum, including the caudate

nucleus and putamen; the globus pallidus or pallidum

which comprises the internal (GPi) and external (GPe)

regions; the subthalamic nucleus (STN); and the substan-

tia nigra divided into two main parts, the pars compacta

(SNc) and pars reticulata (SNr). The ventral division of

the BG is associated with limbic functions and consists

of the ventral striatum and nucleus accumbens, the ven-

tral pallidum and ventral tegmental area (Blandini et al.,

2000; Bolam et al., 2000; Parent et al., 2000).

2.1. Functional basal ganglia circuit

The striatum, the input structure of the BG, receives

two major inputs:

1. a massive excitatory glutamatergic projection from

m

e

*Co

Cen

654-

ost areas of the cerebral cortex organized in a

ighly topographical manner, and
h
2. a dopaminergic projection from the SNc (Parent

t al., 1995b, 2000; Smith et al., 1998; Bolam

t al., 2000).
e
The striatum also receives glutamatergic inputs from

the amygdala, the hippocampus and the centromedian–

rrespondence to: Dr The re se Di Paolo, Molecular Endocrinolo

ter (CHUL), 2705 Laurier Boulevard, Que bec PQ, G1V 4G2,

2296; Fax: 418-654-2761.

parafascicular thalamic complex (Parent et al., 2000;

Smith et al., 2004) and serotoninergic afferents from

the raphe and caudal linear nuclei (Parent et al.,

1995b; Blandini et al., 2000). In addition, the activity

of the BG components in controlling movements is

modulated by the pedunculopontine nucleus (PPN)

(Delwaide et al., 2000; Parent et al., 2000).

The mammalian striatum has two anatomical com-

partments: the striosomes (patches) and the matrix

with distinct chemical compositions and connections

(Graybiel et al., 2000; Prensa and Parent, 2001; Lev-

esque et al., 2004). High densities of m opioid receptor

binding and low levels of acetylcholinesterase staining

define striosomes, while the matrix has high levels of

the Ca2þ-binding protein, calbindin (Graybiel and

Ragsdale, 1978). Striosomes express a higher density

of gamma-aminobutyric acid (GABA)A receptor com-

pared to the matrix (Waldvogel et al., 1999). The areas

of cortex associated with the limbic system innervate

striosomes whereas the neocortical inputs to the matrix

originate from the association and sensorimotor cor-

tices, which innervate medial and lateral parts of the

striatum, respectively (Graybiel et al., 2000). It has

been suggested that the balance of activity between

the matrix and striosomal compartments has an impor-

tant role in the modulation of BG motor functions

(Graybiel et al., 2000).

The principal output nuclei of the BG are SNr and

GPi (Parent and Hazrati, 1995a, b; Parent et al.,

2000). These nuclei, SNr and GPi, tonically inhibit the

ventral anterior and ventral lateral (VA/VL) motor

nuclei of the thalamus, thereby reducing excitatory

thalamic innervation of cortical motor areas (Alexander

and Crutcher, 1990). Movement occurs when the

gy and Oncology Research Center, Laval University Medical

Canada. E-mail: [email protected], Tel: 418-

mailto:[email protected]

DI

thalamus is disinhibited, facilitating excitation of corti-

cal motor areas and resulting in increased motor output

to the brainstem and spinal cord (Pollack, 2001).

According to the current model for the organization

of the BG, the cortical information is received by stria-

tal medium spiny neurons. These neurons relay this

information to the SNr and GPi via direct and indirect

pathways. In the direct pathway, GABA containing

medium spiny neurons project directly to the output

nuclei (SNr-GPi). These striatonigral neurons also

express dopamine D1 receptors, the neuropeptides sub-

stance P (SP) and dynorphin (Dyn). Stimulation of the

direct pathway inhibits the target neurons in SNr-GPi,

thus facilitating the thalamocortical activity by disinhi-

bition of the thalamus. This facilitatory action of the

direct pathway is modulated by the indirect pathway.

In the indirect pathway, the GABAergic medium spiny

neurons project indirectly to the output nuclei via a

complex network interconnecting the GPe and STN.

These GABAergic medium spiny neurons express

dopamine D2 receptors and the neuropeptide

enkephalin (Enk) and project directly to the GPe (stria-

topallidal neurons). The GPe sends GABAergic projec-

tions to the STN or sends direct projections to the

SNr-GPi (Alexander and Crutcher, 1990; Wichmann

and DeLong, 1996; Bolam et al., 2000; Parent et al.,

2000; Hornykiewicz, 2001). The segregation of the

striatonigral (direct) and striatopallidal (indirect) path-

ways is not complete; indeed, striatonigral neurons give

minor axon collaterals to the globus pallidus (GPe in

primates) (Kawaguchi et al., 1990). A subpopulation

of GPe neurons sends an inhibitory feedback selectively

to the striatal GABAergic interneurons. Cortical input is

also received by these inhibitory interneurons, which in

turn innervate medium spiny neurons. Thus, by syn-

chronizing the activity of medium spiny neurons, these

neurons are in the position to modulate the flow of

cortical information through the BG (Bolam et al.,

2000).

Disinhibition of STN by pallidal projection neurons

leads to glutamate-mediated excitation of the output

nuclei. Consequently, inhibitory control over the thala-

mus increases and motor activity decreases. The STN

sends projection neurons to GPe and output nuclei of

the BG. Besides inhibitory GABAergic neurons from

GPe, the STN also receives inhibitory projections from

ventral pallidum and nucleus accumbens, excitatory

input from PPN, parafascicular nucleus of the thala-

mus, the sensory motor cortex and dopaminergic

inputs from SNc. In the current models of BG circui-

try, the STN holds a strategic position in the circuitry

(Alexander and Crutcher, 1990; Wichmann and

DeLong, 1996; Smith et al., 1998; Bolam et al.,

2000; Parent et al., 2000; Hornykiewicz, 2001).

20 P. SAMA

Voluntary movement is mediated by a balanced

activity of the direct and indirect pathways. In con-

trast, imbalance in the activity of these two pathways

and the resulting alterations in the output nuclei are

thought to account for the hypo- and hyperkinetic fea-

tures of BG disorders (Bedard et al., 1999; Parent

et al., 2000). The major connections of the BG struc-

tures are summarized in Fig. 2.1.

2.2. Chemical transmission systems in thebasal ganglia

More than 99% of all synapse in the brain use chemi-

cal transmission, referred to as fast and slow synaptic

transmission (Greengard, 2001). Neuronal activity in

the BG is under the control of different neurotransmit-

ter systems that regulate the duration and intensity of

cellular communications.

In recent years, it has become clear that information

exchange at the synapse is bi-directional. In classical

anterogade signaling neuronal information coded by

the action potential is transmitted through a chemical

synapse in the anterograde direction by release of neu-

rotransmitters, neuropeptides and neuromodulators

from the presynaptic terminal. The transmitter mole-

cules then diffuse across the synaptic cleft and bind

to their receptors on the postsynaptic cell membrane.

This in turn activates the receptors, leading to immedi-

ate changes in membrane potential as well as long-term

structural and metabolic changes in the postsynaptic

cell. This form of transmission has the important prop-

erty of amplification and, by the discharge of just one

synaptic vesicle, several thousand molecules of trans-

mitter stored in that vesicle are released. Because of

the rapid dynamic of synthesis and release, much of

the small transmitter molecules in the neuron must be

synthesized at the terminal. In contrast, the protein

precursors of neuroactive peptides are only synthe-

sized in the cell body where they are packaged in

dense-core vesicles and transported anterogradely

from the cell body to the terminals. The co-release of

several neuroactive substances on to appropriate post-

synaptic receptors allows an extraordinary diversity

of information to be transferred in a single synaptic

action (Kandel et al., 2000). In recently discovered

retrograde signaling, the postsynaptic cell provides a

variety of retrograde signals either constitutively or

triggered by synaptic activity on the postsynaptic neu-

ron. The retrograde signaling could occur through: (1)

signaling by membrane-permeant factors; (2) signaling

by secreted factors; and (3) signaling by membrane-

bound factors. The retrograde signaling is now recog-

nized as a mechanism of synaptic regulation in the

brain where it plays a critical role in the differentiation

ET AL.

Cerebral cortex

ThalamusStriatum

D2/A2AEnk

D1/A1Dyn, SP

SNr/GPi

PPN

GPe SNc

DADA

DA

Brainstem andspinal cord

Raphe nuclei

STN

5-HTDAGluGABAGlu and/orACh

++

++

+

+ + + +

5-HT

+

+

-

-

--

-

-

-

Fig. 2.1. Major circuits of the basal ganglia. GPi, internal globus pallidus; GPe, external globus pallidus; PPN, pedonculopon-

tine tegmental nucleus; STN, subthalamic nucleus; SNc, substantia nigra pars compacta; SNr, substantia nigra pars reticulata;

5-HT, serotonin; DA, dopamine; Glu, glutamate; GABA, gamma-aminobutyric acid; ACh, acetylcholine; Enk, enkephalin;

Dyn, dynorphin; SP, substance P.

FUNCTIONAL NEUROCHEMISTRY OF THE BASAL GANGLIA 21

and maintenance of presynaptic cells, as well as in the

formation, maturation and plasticity of the synapse

(Fitzsimonds and Poo, 1998; Tao and Poo, 2001;

Alger, 2002).

Transmitters are removed from the synaptic cleft by

three different mechanisms: diffusion, enzymatic

degradation and reuptake by specific neurotransmitter

transporters (Kandel et al., 2000).

The processing and storage of motor information in

the BG depend on the signal transduction induced by

different neurotransmitters and neuromodulators.

Table 2.1 summarizes the most important of these che-

mical messengers in the BG.

2.3. Dopamine

The mesostriatal dopaminergic pathway is composed

of: (1) the dorsal part, corresponding to the dopami-

nergic nigrostriatal projection of the SNc; and (2) theventral part, corresponding to the dopaminergic neu-

rons of the ventral tegmental area, which terminates

in the ventral striatum (Parent et al., 1995b). The role

of dopamine as the main neurotransmitter in the func-

tional organization of the BG is drawn from the severe

motor disturbances resulting from the degeneration of

the nigrostriatal pathway in Parkinson’s disease (PD)

(Marsden, 1984). Dopaminergic innervation of the

STN and GPi originating from the SNc has been also

demonstrated (Cossette et al., 1999).

Dopaminergic and glutamatergic systems interact

closely at the level of medium spiny neurons. Dopami-

nergic nigrostriatal neurons synapse mainly on to the

necks of dendritic spines of medium spiny projection

neurons (Smith and Bolam, 1990b; Hanley and Bolam,

1997) whereas glutamatergic cortical afferents synapse

specifically on the head of the same dendritic spines

(Smith et al., 1994). These findings suggest that gluta-

mate activates medium spiny neurons while dopamine

released from the nigrostriatal terminal acts on dopa-

mine receptors within the synapse and extrasynaptic

sites to modulate striatal glutamatergic input (Starr,

1995; Yung et al., 1995; Pollack, 2001). In addition,

recent studies suggest that dopamine may also modu-

late striatal interneuron activity. Since the activity of

medium spiny neurons is also finely regulated by

interneurons, by modulating the activity of these inter-

neurons dopamine exerts an indirect but potent control

on the striatal output neurons (Bracci et al., 2002; Cen-

tonze et al., 2003b). Therefore, dopamine, by provid-

ing strong modulation of striatal neuronal activity,

plays an important role in the control of the whole

BG circuitry and ensures voluntary movements.

Table 2.1

Major neurotransmitters and neuromodulators in the basal ganglia and their receptors

Neurotransmitter/neuro-

modulator Ionotropic receptor Metabotropic receptor

Dopamine D1, D2, D3, D4, D5

Glutamate NMDA

subunits:

AMPA

subunits:

Kainate

subunits: Group I Group II Group III

NR1 GluR1 GluR5 mGluR1 mGluR2 mGluR4

NR2A GluR2 GluR6 mGluR5 mGluR3 mGluR6

NR2B GluR3 GluR7 mGluR7

NR2C GluR4 KA1 mGluR8

NR2D KA2

NR3A

GABA GABAA, GABAC GABAH(GABABR1 - GABABR2)

Acetylcholine Nicotinic Muscaritic (M1, M2, M3, M4, M5)

Adenosine A1, A2A, A2B, A3

Cannabinoid CB1, CB2, CB3?

Serotonin 5-HT3

5-HT1A, B, D, E, F; 5-HT2A, B, C,

5HT4; 5-HT5A, B; 5-HT6; 5-HT7

Neurokinins (NKs)

(Substance P/NK-1,

Substance K/NK-2,

Neuromedin K/NK-3)

NK-1R (SPR),

NK-2R (SKR),

NK-3R (NKR)

Opioids (Enlephalin;

Dynorphin) m, k, d

Neurotensin NTS1, NTS2, NTS3

Neuropeptide Y (NPY) NPYRs (6 known receptors)

Somatostatin (SOM) SSTRs (5 known receptors)

Angiotensin AT1, AT2, AT3

Cholecystokinin CCKAR, CCKBR

22 P. SAMADI ET AL.

2.3.1. Dopamine biosynthesis, reuptake and

degradation

The precursors of dopamine, phenylalanine and tyro-

sine, but not dopamine itself, are able to cross the

blood–brain barrier. The biosynthesis of dopamine

takes place within the cytosol of nerve terminals in

two steps. First, tyrosine is converted to levodopa

(l-dihydroxyphenylalanine) by the enzyme tyrosine

hydroxylase, which is present in catecholamine-

containing neurons. Then, dopamine is synthesized

from decarboxylation of levodopa by the enzyme

dopa-decarboxylase, also known as aromatic amino

acid decarboxylase (AADC). Dopamine is finally

degraded by the activity of monoamine oxidase

(MAO) and aldehyde dehydrogenase to dihydroxyphe-

nylacetic acid (DOPAC). Dopamine can also be

metabolized by the enzymatic activity of catechol-O-methyltransferase to form 3-methoxytryptamine. DOPAC

and 3-methoxytryptamine are then degraded to form

homovanillic acid (Webster, 2001b; von Bohlen und

Halbach and Dermietzel, 2002). The summary of the

synthesis, transport and degradation of dopamine is

illustrated in Fig. 2.2.

Glial cell

DA

DA

DA

3-MT

HVA

L-DOPA

Tyrosine

CO

MT

DA

AADC

DAT

TH

VMAT2

Presynapticdopaminergic terminal

DOPAC

CO

MTM

AO

HVA

3-MT

DOPAC

CO

MT

MAO

COMT

Fig. 2.2. Schematic illustration of the synthesis, release, transport and degradation of dopamine in dopaminergic nerve

terminals. TH, tyrosine hydroxylase; L-DOPA, L-dihydroxyphenylalanine; AADC, amino acid decarboxylase; DA,

dopamine; MAO, monoamine oxidase; COMT, catechol-O-methyl transferase; DOPAC, 3,4-dihydroxyphenylacetic acid;

3-MT, 3-methoxytyramine; HVA, homovanillic acid; DAT, membrane dopamine transporter; VMAT2, vesicular monoamine

transporter 2.


The dopamine transporters, which are key factors in

the control of extracellular dopamine concentrations,

can be classified into two main families: (1) the mono-

amine vesicular transporter (VMAT2) and (2) plasma

membrane transporter (dopamine transporter (DAT)).

VMAT2 is distinct from VMAT1 in the adrenal

medulla and is responsible for packaging dopamine

and other monoamines from cytoplasm into synaptic

vesicles. Reduction of VMAT2 binding in the nigros-

triatal system has been demonstrated in animal models

of PD (Vander Borght et al., 1995; Kilbourn et al.,

2000), and has also been reported in patients with

PD (Frey et al., 1996). The vesicular monoamine

uptake, including dopamine, involves the exchange of

lumenal Hþ for cytoplasmic transmitters by Hþ-ATPase located in the vesicular membrane (Piccini,

2003).

DAT is responsible for the uptake of dopamine

from the extracellular space into the cytoplasm (Pic-

cini, 2003). Like other monoamine transporters, DAT

is a transmembrane protein, containing 12 putative

domains. The mechanism by which DAT mediates

dopamine uptake involves sequential binding and

cotransport of two Naþ ions and one Cl� ion generated

by the plasma membrane Naþ/Kþ-ATPase (Torres

et al., 2003). DAT functions are regulated by presynaptic

receptors, protein kinases and membrane trafficking and

changes in DAT levels can clearly alter motor

activity (Marshall and Grosset, 2003; Schenk et al.,

200; Uhl, 2003). Agents that alter protein kinase C

(PKC), inositol triphosphate (PI3) kinase and mitogen

and signal-regulated kinase (MEK1 and 2) alter DAT

function (Vrindavanam et al., 1996; Carvelli et al.,

2002; Uhl, 2003). Transporters can also function in

reverse and they possess channel-like activity (Torres

et al., 2003).

Since PD is a progressive neurodegenerative disease,

neuroimaging techniques that reflect the conversion of

levodopa to dopamine through aromatic AADC,

VMAT2 and DAT, can be used to evaluate the status

of the nigrostriatal dopaminergic system (Brooks

et al., 2003). Furthermore, DAT and VMAT2 localiza-

tion provides markers for presynaptic dopaminergic loss

in parkinsonism and allows parkinsonism to be differen-

tiated from other movement disorders without presy-

naptic dopaminergic loss, such as essential tremor,

DI

vascular pseudoparkinsonism and psychogenic parkin-

sonism (Marshall and Grosset, 2003).

2.3.2. Receptors and signal transduction

Dopamine receptors belong to the seven transmembrane-

like G-protein-coupled receptor superfamily. According

to the similarity of a-subunits, G-proteins are divided

into four main families: Gas/olf, Gai/o, Gaq/11 and

Ga12/13. Each family preferentially regulates specific

classes of effector molecules, for example Gas/olf andGai/o are positively and negatively coupled to adenylyl

cyclase, respectively (Cabrera-Vera et al., 2003). To date,

five distinct dopamine receptors subtypes (D1–D5) have

been isolated and characterized (Missale et al., 1998).

These receptors are classified into two main families:

D1-like (D1 and D5) and D2-like (D2–D4) dopamine

receptors, based on positive (D1) or negative (D2)

coupling to adenylyl cyclase and the regulation of intra-

cellular cyclic adenosine monophosphate (cAMP) levels

(Kebabian and Calne, 1979; Missale et al., 1998). Dopa-

mine, through activation of D1-like receptors and

cAMP-dependent protein kinase A (PKA) phosphory-

lates a key component of dopaminergic signaling in med-

ium spiny neurons, the dopamine- and cAMP-regulated

phosphoprotein (DARPP-32) at threonine 34 (Thr-34).

The phosphorylation converts DARPP-32 from an inac-

tive molecule into an inhibitor of protein phosphatase-

1 (PP-1), which controls the state of phosphorylation

and activity of numerous physiologically important

effectors, including transcription factors such as cAMP

response element-binding protein (CREB), fos-family,

ion channels and ionotropic receptors. Conversely,

activation of D2-like receptors counteracts the effect

of D1-like receptors on phosphorylation of DARPP-

32 at Thr-34 by activating PP-2B and by reducing

cAMP levels (Nishi et al., 1997; Greengard, 2001).

D1-like receptors could also act on inositol phosphate

production and mobilization of intracellular Ca2þ

(Undie et al., 1994). On the other hand, D2-like recep-

tors suppress N-type Ca2þ currents (Yan et al., 1997).

Although D1 and D2 receptors in the striatum

appear to be largely segregated, there is evidence of

co-localization of D1 and D2 receptors on medium

spiny neurons (Surmeier et al., 1996; Aizman et al.,

2000), the collateralization of striatofugal axons

(Parent et al., 1995a, 2000), and the presence of D2

receptors on striatal interneurons (Betarbet et al.,

1997). D1 receptors may be exclusively localized on

postsynaptic elements in striatal medium spiny neu-

rons (Hersch et al., 1995; Caille et al., 1996), while

D2 receptors are reported to be localized on pre- and

postsynaptic elements, including corticostriatal term-

inals (Hersch et al., 1995; Wang and Pickel, 2002).

24 P. SAMA

Recent studies revealed that dopamine selectively inhi-

bits particular subsets of corticostriatal afferents via

activation of D2 receptors on glutamatergic presynap-

tic terminals (Bamford et al., 2004). Inactivation of

L-type voltage-dependent Ca2þ channels is a main

mechanism involved in the D2 receptor-mediated inhi-

bition of striatopallidal neuronal activity (Hernandez-

Lopez et al., 2000).

GABAergic interneurons which have dense arbori-

zation and contact several striatal neurons, including

interneurons themselves, also express D2 receptors

(Delle Donne et al., 1997). It has been shown that

D2 receptors cause presynaptic inhibition of both

GABAergic and cholinergic interneurons (Pisani

et al., 2000).

By a mechanism of alternative splicing, the D2

receptor genes encode two isoforms, D2L and D2S

(Usiello et al., 2000). These two isoforms have different

functions in vivo; D2S is principally a D2 presynaptic

autoreceptor, while D2L acts mainly at postsynaptic

sites (Usiello et al., 2000). The D3 receptor has a higher

expression in nucleus accumbens while is less

expressed in the dorsal striatum (Levesque et al.,

1992; Missale et al., 1998). Moderate levels of D4

receptor expression in dorsal striatum with greater

abundance in striosome than in matrix has been shown

(Rivera et al., 2002b). It has been reported that D4

receptors are located on corticostriatal projections to

the dorsal and ventral striatum (Tarazi et al., 1998).

The expression of D5 receptor in the striatum has been

demonstrated (Yan and Surmeier, 1997; Rivera et al.,

2002a) and is reported to be preferentially expressed

in striatal interneurons (Rivera et al., 2002a).

A variety of G-proteins, ion channels and second

messenger systems modulated by dopamine receptor

activation can induce both immediate and long-term

changes in cell physiology (Sealfon and Olanow,

2000). Dopamine D1 and D2 receptors on striatal med-

ium spiny neurons serve to modulate glutamate-

mediated activity (Calabresi et al., 2000a). The D1

receptor activation produces different effects on Ca2þ

currents, reducing N- and P-type but enhancing L-type

conductances (Surmeier et al., 1995). Dopamine

potentiates NMDA-induced currents in medium spiny

neurons by enhancement of L-type Ca2þ conductances

and the cAMP-dependent PKA and PKC cascades

(Smart, 1997; Cepeda et al., 1998). Recently, it has been

reported that the D1 and D5 dopamine receptor activa-

tion induces long-term potentiation (LTP) and long-term

depression (LTD) in distinct subtypes of striatal neurons

and could exert distinct roles in motor activity and cor-

ticostriatal synaptic plasticity (Centonze et al., 2003a).

According to these studies, while LTP induction

requires the stimulation of the D1-PKA pathway in the

ET AL.

TR

medium spiny neurons, LTD depends on the activation

of D5-PKA signaling in a neuronal subtype other than

medium spiny neurons (Centonze et al., 2003a).

The homo- and heterodimerization of G-protein-

coupled receptor can generate numerous possibilities

in the regulation of their function (Bouvier, 2001).

Dopamine D2 receptor homodimerization (Lee et al.,

2003) and also heterodimerization of D2/D3 (Maggio

et al., 2003), dopamine/somatostatin (Rocheville et al.,

2000) and dopamine/adenosine (Franco et al., 2000)

receptor families have been shown. These receptor

homo- and heterodimerizations might be involved in

the development of neuronal plasticity contributing to

learning and memory (Franco et al., 2000).

2.4. Glutamate

The striatum receives glutamatergic projections from

the cortex and the thalamus. The corticostriatal affer-

ents are the main extrinsic pathways of the BG and

they are highly topographic and impose a functional

compartmentation of striatal regions. The STN is the

principal intrinsic glutamatergic structure of these

brain nuclei. Despite its relatively small size,

the STN is currently considered as one of the main

driving forces of the BG (Parent et al., 1995b; Parent,

2002).

FUNCTIONAL NEUROCHEMIS

Glu

Glu

Gln

Glu VGLUT

Presynapticglutamatergic terminal

Glucose

Glutaminase

Fig. 2.3. Schematic representation of the biosynthesis, release, tr

terminal. Glu, glutamate; Gln, glutamine; EAAT, excitatory amin

2.4.1. Glutamate biosynthesis and reuptake

L-glutamic acid or glutamate is the most abundant exci-

tatory neurotransmitter in the brain. Glutamate cannot

cross the blood–brain barrier and therefore it is synthe-

sized locally from glucose via pyruvate, the Krebs cycle,

the transmission of a-oxoglutamate or by deamination

of glutamine in nerve terminals. Glutamate is then accu-

mulated in synaptic vesicles (Dickenson, 2001; von

Bohlen und Halbach and Dermietzel, 2002). After

release, the high-affinity membrane transporters

remove glutamate from the synapse into the nerve

terminals or into the adjacent glial cells. The imported

glutamate in glial cells is converted to glutamine by glu-

tamine synthetase. Glutamine is then released from the

glial cells by glutamine transporter for subsequent

uptake by glutamate nerve terminals. Glutamine is then

transformed into glutamate by neuronal mitochondrial

glutaminase (Dickenson, 2001; von Bohlen und

Halbach and Dermietzel, 2002). The summary of the

synthesis, transport and degradation of glutamate is illu-

strated in Fig. 2.3.

The storage of glutamate in synaptic vesicles

requires the presence of vesicular glutamate transpor-

ter (VGLUT), which is independent of Naþ and Kþ

and requires Hþ-ATPase exchange (Danbolt, 2001;

Montana et al., 2004). Three isoforms of VGLUT have

Y OF THE BASAL GANGLIA 25

Glial cell

Glu

Gln

Glutam

ine

synthase

EAAT

EAA

T

ansport and degradation of glutamate in glutamatergic nerve

o acid transporter; VGLUT, vesicular glutamate transporter.

DI

been identified in glutamatergic neurons and also in

subpopulations of GABAergic, cholinergic and monoa-

minergic neurons (Bai et al., 2001; Fremeau et al.,

2002; Gras et al., 2002; Dal Bo et al., 2004). The

cotransmission of glutamate in dopamine neurons may

provide novel insight into pathophysiological processes

that underlie PD (Plaitakis and Shashidharan, 2000; Dal

Bo et al., 2004). Furthermore the glial cells, astrocytes,

could modulate synaptic transmission by releasing glu-

tamate in a Ca2þ-dependent manner (Kang et al.,

1998) and recent studies suggest that VGLUTs also

play a functional role in exocytotic glutamate release

from astrocytes (Montana et al., 2004).

The only rapid way to remove the glutamate

released from nerve terminals by exocytosis is the

reuptake of glutamate from the extracellular space.

Until now, a family of five high-affinity uptakes of

the excitatory amino acid transporters (EAATs) have

been identified (Danbolt, 2001). These cytoplasmic

membrane transporters are located presynaptically in

glutamatergic nerve terminals, postsynaptically in den-

drites and spines and extrasynaptically in glial cells.

The EAATs termed EAAT1–EAAT5 cotransport Naþ

and Hþ into the cells in the exchange of Kþ and they

are also called Naþ- and Kþ-coupled glutamate trans-

porters. In addition, postsynaptic glutamate transpor-

ters have a relatively high associated Cl� channel

activity (Danbolt, 2001). In the rat striatum, glutamate

aspartate transporter (GLAST, EAAT1) and GLT1

(EAAT2) are expressed in astrocytes and EAAC

(EAAT3) in neurons (Danbolt, 2001). A lesion of glu-

tamatergic corticostriatal projection has been shown to

downregulate the GLT1 and GLAST (Levy et al.,

1995a). However, nigrostriatal denervation in the rat

model of PD does not affect GLT1 mRNA expression,

although chronic levodopa treatment increases GLT1

mRNA and protein expression in this model. This

effect is suggested to be a compensatory mechanism

involving astrocytes in order to prevent neurotoxic

overactivity of glutamate (Lievens et al., 2001; Robe-

let et al., 2004). Furthermore, it has recently been

shown that the inhibitory influence of A2A receptor

activation on glutamate uptake may be one of the

putative mechanisms responsible for the neuropro-

tective effects of A2A receptor antagonists in the

striatum (Popoli et al., 2002; Pintor et al., 2004).

Accordingly, all these results indicate the important

role of glutamate transporters in neurodegenerative

processes that underlie PD.


Glutamate receptors (GluRs) are classified into two

main groups of ionotropic or metabotropic receptors

26 P. SAMA

based on their structure and mechanisms of action

(Stone and Addae, 2002).

ET AL.

2.4.2.1. The ionotropic glutamate receptors

These receptors are ligand-gated ion channels (Glu-sen-

sitive) and open on activation, allowing the influx of

Naþ, Kþ and/or Ca2þ, which subsequently mediate fast

excitatory synaptic transmission. Three subtypes of

ionotropic glutamate receptors have been identified:

N-methyl-d-aspartate (NMDA), a-amino-3-hydroxy-5-

methyl-4-isoxazole propionic acid (AMPA) and kainate

(Dingledine and McBain, 1999; Dickenson, 2001; von

Bohlen und Halbach and Dermietzel, 2002). The NMDAreceptors consist of a combination of at least four sub-

units belonging to three families: NMDA R1 (NR1),

NMDA R2 (NR2A, NR2B, NR2C and NR2D) and

NR3A (Mori andMishina, 1995; Das et al., 1998; Laube

et al., 1998). NR1 subunits are ubiquitous to all NMDA

receptors and are necessary for their function. In addi-

tion to the conventional agonist-binding site occupied

by glutamate, the binding of glycine at a co-agonist

site is required for receptor activation (Kleckner and

Dingledine, 1988). Additionally, unlike the non-NMDA

receptor channels, NMDA receptor channels are physio-

logically blocked by Mg2þ at resting membrane

potential and the NMDA channel opening requires simul-

taneous occurrence of neurotransmitter binding and mem-

brane depolarization. In addition, the receptor is highly

permeable to Ca2þ, a well-known second messenger able

to activate multiple signaling cascades and long-lasting

changes in regulation of gene expression (Ghosh and

Greenberg, 1995; Finkbeiner and Greenberg, 1998).

These unique properties of NMDA receptors indicate

their important physiological functions such as synaptic

plasticity and synapse formation, which determine learn-

ing and memory (Yamakura and Shimoji, 1999). TheAMPA receptors are hetero-oligomeric proteins made of

the subunits GluR1–GluR4. Each receptor complex is

thought to contain four subunits (Rosenmund et al.,

1998). Finally, the kainate receptors are heteromeric

combinations of the high-affinity kainite-binding

subunits (GluR5–7 and Kainate1–2) (Hollmann and Hei-

nemann, 1994). The AMPA and kainate receptors have

permeability to Naþ and Kþ and, based on the RNA-

editing sites, some of them are permeable to Ca2þ

(Gu et al., 1996). Striatal ionotropic glutamate receptors

could regulate mitogen-activated protein kinase

(MAPK) cascades that contribute to the development

of neuroplasticity (Wang et al., 2004). Electrical

or chemical stimulation of corticostriatal pathways

induce phosphorylation of ERK1/2, which is one of

the MAPK subfamilies in striatal neurons involved in

response to glutamate (Sgambato et al., 1998). Activation

TR

of all three subtypes of ionotropic glutamate receptors is

believed to possess the ability to phosphorylate ERK1/2

(Wang et al., 2004). Pharmacological activation of

NMDA receptors strongly increases ERK1/2 activation

in striatal neurons and this effect is sensitive to NMDA

receptor antagonists (Perkinton et al., 2002; Mao et al.,

2004). The NMDA receptor is believed to initiate its acti-

vation of ERK1/2 via Ca2þ influx since the absence or

low concentrations of extracellular Ca2þ impair NMDA

activation of ERK1/2 (Perkinton et al., 2002). Ca2þ-cal-modulin-dependent protein kinase II (CAMKII),

a major Ca2þ-sensitive kinase, relays Ca2þ signals in

the postsynaptic NMDA receptor complex (Wang et al.,

2004). Interestingly, more recent studies reveal that the

CAMKII hyperphosphorylated state plays a causal role

in the pathophysiology of parkinsonian motor disability

and in the maladaptive striatal plasticity after dopamine

denervation (Picconi et al., 2004).


2.4.2.2. The metabotropic glutamate receptors

The metabotropic glutamate receptors (mGluRs)

belong to G-protein-coupled receptor family 3, which

also includes GABAB receptors. These receptors mod-

ulate excitatory synaptic transmission by at least two

mechanisms: first, an inhibition of glutamate release

from afferent nerve terminals, and second, a regulation

of the activity of voltage-dependent ion channels or

ionotropic glutamate receptors (particularly NMDA

receptors) at postsynaptic sites (Picconi et al., 2002).

The mGlu receptors are classified into three groups.

Group I, including mGluR1 and 5, are positively

linked to the activation of phospholipase C and PI3hydrolysis via Gq. Their activation leads to an increase

in intracellular Ca2þ levels, stimulation of PKC,

potentiation of L-type voltage-dependent Ca2þ chan-

nels and inhibition of Kþ conductances that generally

mediate postsynaptic excitatory effect (Conn and Pin,

1997; Gubellini et al., 2004). Group II (mGluR2, 3)and group III (mGluR4, 6–8) mGlu receptors are

negatively coupled to adenylyl cyclase via Gi/Go, or

pertusis toxin-sensitive G-protein, respectively. Their

activation inhibits the formation of cAMP and also

exerts an inhibitory action on L-N and P/Q type of

voltage-dependent Ca2þ channels and activates

hyperpolarizing Kþ conductance. In addition, pharma-

cological blockade of mGluR1 or mGluR5, or pharma-

cological activation of mGluR2/3 or mGluR4/7/8,

produces neuroprotection shown in a variety of central

nervous system (CNS) disorder models (Bruno et al.,

2001). These receptors are generally found presynapti-

cally where they exert an inhibitory action on the release

of glutamate and other neurotransmitters (Cartmell and

Schoepp, 2000; Gubellini et al., 2004).

Furthermore, mGlu receptors also have the potential

to regulate the MAPK pathway. It has been shown that

intracaudate injection of a group I mGlu receptor ago-

nist upregulates ERK1/2 phosphorylation (Choe and

Wang, 2001). However, currently there are no available

data regarding the influence of group II and III mGlu

receptors on striatal MAPK cascades (Wang et al.,

2004). The interaction between mGlu receptors and

other G-protein-coupled receptors, in particular dopa-

mine, adenosine and muscarinic acetylcholine recep-

tors, has also been demonstrated (Pin and Acher,

2002; Moldrich and Beart, 2003; Gubellini et al., 2004).


2.4.2.3. Glutamate receptors in the BG

NR1 subunit mRNA is expressed in the striatum, STN

and SNc, whereas in globus pallidus (GPe, GPi and

ventral pallidum) and SNr the mRNA expression of

NR1 subunit is less intense (Ravenscroft and Brotchie,

2000). Although all striatal neurons express NMDAR2

receptors, their subunit expressions are different

among various neuronal populations. NR2B mRNA

is expressed prominently over all striatal neurons (cau-

date and putamen). NR2A mRNA is of relatively

lower abundance in the striatum. While no labeling

for NR2A is observed on somatostatinergic and choli-

nergic interneurons, it is expressed over glutamic acid

decarboxylase (GAD) 67 immunoreactive neurons.

NR2D mRNA expression has been observed strongly

in the globus pallidus (GPe and GPi) and moderately

in the striatum. NR2C mRNA is expressed weakly all

over striatal neurons, except for a moderate expression

in cholinergic interneurons (Kosinski et al., 1998;

Kuppenbender et al., 2000; Smith et al., 2001). As

the NMDA receptor complex represents a key molecu-

lar element in motor abnormalities in PD, the pattern

of NMDA receptor expression should be considered

for therapeutic approaches targeting specific NMDA

receptor subtypes in PD.

In the human striatum, which is enriched in AMPA

receptors, both striatal output projection neurons and

large interneurons express GluR1, GluR2 and GluR3

subunits. However, the GluR4 subunit expression is

restricted to a small population of large and medium-

sized neurons (Bernard et al., 1996; Tomiyama et al.,

1997; Smith et al., 2001). AMPA and NMDA receptor

subunits are also expressed at subthalamopallidal glu-

tamatergic synapses in the globus pallidus (Clarke

and Bolam, 1998).

In the monkey striatum kainate receptors (GluR6/7

and kainate-2) are expressed intracellularly in presy-

naptic glutamatergic terminals and may control gluta-

mate release from the thalamus and cerebral cortex.

Postsynaptic kainate receptors are also expressed in

DI

dendrite and spine throughout the striatum (Charara

et al., 1999; Kieval et al., 2001). On the other hand,

more than 60% of pre- and postsynaptic plasma mem-

brane kainate receptors are expressed extrasynaptically

(Kieval et al., 2001). The roles of kainate receptors in

the striatum and the exact mechanism by which kainic

acid has toxic effects on striatal projection neurons are

still poorly understood. However, it has been demon-

strated that the activation of presynaptic kainate recep-

tors like postsynaptic kainate receptors may lead to

increased Naþ and Ca2þ conductances and conse-

quently to the depolarization of nerve terminals. This

could facilitate the opening of voltage-dependent Ca2þ

channels and potentiate glutamate release with excito-

toxic effects (Perkinton and Sihra, 1999). Other studies

have demonstrated that kainate receptors in the monkey

striatum could downregulate GABAergic synaptic

transmission indirectly via release of adenosine (acting

on A2A receptors) (Chergui et al., 2000). Since kainate

receptors are also expressed extrasynaptically and their

metabotropic-like functions have also been reported

(Rodriguez-Moreno and Lerma, 1998), it was suggested

that these receptors probably mediate slow modulatory

effects rather than fast synaptic transmission (Kieval

et al., 2001). Recent studies reveal that the density of

kainate receptors is increased in the striatum of 6-

hydroxydopamine (6-OHDA) rats (Tarazi et al., 2000).

Interestingly, AMPA and kainate receptor antagonists,

but not NMDA antagonists, are known to protect dopa-

minergic terminals of rat striatum against 1-methyl-4-

phenylpyridinium ion (MPPþ) toxicity. Further investi-gations in animal models of PD are needed to clarify

the role of these receptors in PD.

The group I mGlu receptors, mGluR1 and mGluR5,

are expressed by striatal medium spiny neurons and by

subpopulations of interneurons, including cholinergic

interneurons (Testa et al., 1994, 1995, 1998; Smith

et al., 2000; Pisani et al., 2001). Recent studies demon-

strated the presynaptic localization of mGluR5 at

dopaminergic synapses and also in glutamatergic term-

inals, preferentially in thalamostriatal over corticos-

triatal afferents (Paquet and Smith, 2003). The

localization of group I mGlu receptors not only at glu-

tamatergic but also at GABAergic striatal synapses in

GPe, GPi and SNr has been shown (Hanson and Smith,

1999). Since mGlu receptors have high affinity for

glutamate, a small amount of spilled-over neurotrans-

mitter could be one of the sources that activate these

receptors. Other possibilities are extrasynaptic diffu-

sion of glutamate released from astrocytes or, under

certain circumstances, glutamate released from striatal

terminals (Smith et al., 2001). At GABAergic

synapses, these postsynaptic mGlu receptors could reg-

ulate GABA currents in pallidal or SNr neurons either

28 P. SAMA

by changing membrane excitability through modulation

of Ca2þ and Kþ channels (Conn and Pin, 1997) or via

direct physical interactions with GABAA or GABAB

receptors (Smith et al., 2001). At STN synapses in

GPe and GPi, activation of presynaptic mGluR1 and 5

by glutamate released from overactive STN could lead

to increased activity of BG output nuclei through var-

ious mechanisms, including potentiation of ionotropic

glutamatergic transmission and reduction of Kþ con-

ductances (Smith et al., 2001). Therefore, antagonists

of group I mGlu receptors has been suggested as a

potential target to reduce the overactivity of pallidal

neurons generated by STN in PD (Pisani et al., 1997;

Ossowska et al., 2002; Picconi et al., 2002). Activation

of mGluR5 (group I) could reduce striatal dopamine

uptake by phosphorylation of the transporter through

activation of CAMKII and PKC (Page et al., 2001).

This regulatory interaction demonstrates that the two

glutamatergic and dopaminergic systems interact

closely in the striatum and glutamate can potentially

regulate dopaminergic transmission.

Group II and III mGlu receptors are mostly found

presynaptically on corticostriatal glutamatergic term-

inals. Furthermore, regarding the high expression of

group II mGluRs in STN neurons and the inhibitory

action of these receptors on glutamate release, the

selective agonists of group II mGlu receptors could

have a beneficial effect in PD by reducing the hyperac-

tivity of excitatory corticostriatal and subthalamopalli-

dal neurons that is developed after dopaminergic

denervation (Rouse et al., 2000; Ossowska et al.,

2002). Accordingly, the alleviation of akinesia after

activation of group III mGluRs in reserpine-treated rats

has been demonstrated (MacInnes et al., 2004).

Although pallidal neurons do not express group II mGlu

receptor mRNA, the mGluR4 and mGluR7 (group III)

are expressed in GABAergic striatopallidal neurons

(Bradley et al., 1999). The group III mGluRs at striato-

pallidal synapses are thought to play a role in modulat-

ing GABAergic transmission at these synapses (Smith

et al., 2000) and the selective agonist of these receptors

could be a target to reduce the parkinsonian syndrome

by attenuation of overactivity of the striato-GPe path-

way. The mGluR2/3 also promote the synthesis and

release of neurotrophic factors in astrocytes (Bruno

et al., 2001). Indeed, these results suggest that appropri-

ate therapeutic interventions with mGlu receptors may

alleviate the symptoms of PD and also delay the pro-

gress of neurodegeneration in this movement disorder.

2.5. Gamma-aminobutyric acid

The amino acid GABA is the main inhibitory neuro-

transmitter in the CNS, including the BG. The principal

ET AL.

TR

neurons in the striatum, i.e. about 77–97.7%, are med-

ium spiny projection neurons, which utilize GABA as

a transmitter (Tepper et al., 2004). These GABAergic

medium spiny neurons are innervated by glutamatergic,

dopaminergic and GABAergic afferent fibers and the

interaction between these inputs at the striatal level

plays an important role in the regulation of the BG

function and in the pathophysiology of PD. The remain-

ing neurons in the striatum are various types of inter-

neurons thought to play an important role in the

processing of information in the striatum. These inter-

neurons have been classified, based on cell diameters,

neurochemistry and physiology, into one population of

large cholinergic interneurons and at least three types

of medium GABAergic interneurons (Kawaguchi et

al., 1995). The two types of GABAergic interneurons

colocalize the Ca2þ-binding protein, parvalbumin or

calretinin and the third class contains somatostatin,

neuropeptide Y, the enzyme nicotinamide adenine

dinucleotide phosphatase (NADPH-d) or nitric oxide

synthase (NOS) (Kawaguchi et al., 1995; Cicchetti

et al., 2000). NOS-containing neurons receive synaptic

inputs from parvalbuminergic interneurons and

innervate striatal output neurons (Morello et al., 1997).

Calretinin interneurons seem to modulate striatal local

circuits in response to inputs from striatal and cortical

neurons (Figueredo-Cardenas et al., 1997). Moreover,

GABA is also the transmitter utilized by GPe and the

output nuclei of the BG (SNr-GPi).

A recent study revealed that in primates, but not in

rodents, GABA is synthesized more in striosome than

in matrix (Levesque et al., 2004). Accordingly, it was

suggested that GABA may have a greater inhibitory

effect on the processing of limbic information than

sensorimotor information which is processed in the

striosome and matrix, respectively (Levesque et al.,

2004).

2.5.1. GABA biosynthesis, transport and

degradation

GABA is synthesized by decarboxylation of gluta-

mate, a reaction catalyzed by the enzyme GAD (Olsen

and Delorey, 1999). GAD exists in two different iso-

forms, termed GAD65 and GAD67, which differ in

their size, cofactor association and subcellular distribu-

tion (Augood et al., 1995). The majority of medium

spiny neurons highly express GAD65 mRNA while

the GABAergic interneurons are preferentially

enriched in GAD67 mRNA (Mercugliano et al.,

1992). Within nerve terminals, GABA, like other neu-

rotransmitters, is stored in synaptic vesicles before its

release into the synaptic cleft (McIntire et al., 1997).

The storage of GABA into vesicles is dependent on


the vesicular GABA transporter containing 520 amino

acids with 10 transmembrane domains (McIntire et al.,

1997; Jin et al., 2003). The transport of GABA into

secretory vesicles relies on the electrochemical proton

gradient created by the Hþ-ATPase (Takamori et al.,

2000; Piccini, 2003).

Specific high-affinity Naþ/Cl�-dependent transpor-ters in both GABAergic and glial cells regulate the

maintenance of the extracellular levels of GABA

(Masson et al., 1999). Four distinct genes encoding

GABA transporters (GATs) have been identified

(Conti et al., 2004). These transporters mediate GABA

uptake, terminating GABA’s action and regulating

GABA’s diffusion to neighboring synapses. In the rat

BG, the globus pallidus, STN and substantia nigra

show high expression of GAT-1 mRNA and also dense

labeling for GAT-1 protein, whereas the dorsal stria-

tum, caudate and putamen show moderate and light

labeling for GAT-1 mRNA and protein, respectively

(Yasumi et al., 1997). The expression of GAT-1 pro-

tein by GABAergic interneurons, containing GAD67

mRNA, is also shown in dorsal striatum (Augood

et al., 1995). Another study in the monkey BG demon-

strates dense labeling of GAT-1 in GPe and GPi, mod-

erate labeling in STN and substantia nigra and low

labeling in the dorsal striatum (Wang and Ong,

1999). Interestingly, the human glutamatergic STN

neurons, coexpressing parvalbumin and/or calretinin,

are also enriched in mRNA encoding GAT-1. This

indicates that the STN neurons may be able to accu-

mulate synaptically released GABA via interaction

with this brain specific high-affinity GABA uptake

protein, in the vicinity of their terminal projections.

This effect may be considered as a potential non-dopa-

minergic target for therapy in PD (Augood et al.,

1999). Expression of GATs, as for glutamate transpor-

ters, is regulated by different factors, including phos-

phorylation of the transporter protein by PKA and

PKC, transcription and activity-dependent trafficking

of transporter protein between the cytosol and plasma

membrane (Bernstein and Quick, 1999; Schousboe,

2003).

GABA is inactivated by transamination with alpha-

ketoglutarate. This reaction is catalyzed by the mito-

chondrial enzyme 4-aminobutyrate aminotransferase

(GABA transaminase; GABA-T). In this process the

amino group from GABA is transferred on to alpha-

ketoglutarate, producing glutamate and succinic acid

semialdehyde. The latter is further metabolized to form

succinic acid, which is an intermediate of the Krebs

cycle. The glutamate formed from the degeneration of

GABA is then converted into glutamine by the cytosolic

enzyme glutamine synthetase. GABA-T is also present

in the mitochondria of glial cells and glial glutamine


Glial cell

GABA

GABA

GABA

Glu

Gln

Glu

Gln

Glutaminesynthase

GABA

GAD65

GAD67

GAT

Glutam

inase

VGAT

PresynapticGABAergic terminal

GABA-T

GA

T

GAB

A-T

KREBSCYCLE

KREBSCYCLE

Fig. 2.4. Diagram showing the synthesis, release, transport and degradation of GABA in a GABAergic nerve terminal. GABA-

T, GABA transaminase; Gln, glutamine; Glu, glutamate; GAT, GABA membrane transporter; VGAT, vesicular GABA trans-

porter; GAD, glutamic acid decarboxylase isoforms 65 and 67.

30 P. SAMADI ET AL.

is an important precursor for both glutamatergic and

GABAergic neurons (Olsen and Delorey, 1999; Farrant,

2001; von Bohlen und Halbach and Dermietzel, 2002).

A summary of the synthesis, transport and degradation

of GABA is illustrated in Fig. 2.4.


Three types of receptors, termed GABAA, GABAB and

GABAC, mediate the effect of GABA in the CNS.

Although GABAA and GABAB are present in the

BG, there is no evidence for the existence of GABAC

in these structures. The fast inhibitory synaptic trans-

mission results from the stimulation of ionotropic

chloride-gated GABAA and GABAC receptor channels

(Macdonald and Olsen, 1994; Johnston, 1996).

GABAA receptors are defined by their sensitivity to

the antagonist bicuculline whereas GABAC receptors

are insensitive to this antagonist. These ionotropic

GABA receptors are composed of a heteromeric struc-

ture consisting of five subunits assembled from a

group of 18 different subunits, which have been char-

acterized in mammalian brain (Barnard et al., 1998;

Waldvogel et al., 2004). The GABAA receptor pos-

sesses three different binding sites. The first one binds

GABA, the second one is a specific binding site for

benzodiazepines and the third binding site is specific

for barbiturates. The two latter sites seem to be absent

from the GABAC receptor (Mehta and Ticku, 1999;

Smith et al., 2001).

Metabotropic GABAB receptors belong to the family

of G-protein-coupled receptors and mediate slow inhibi-

tory synaptic transmission via an increase in Kþ currents

(Bettler et al., 1998; Galvan et al., 2004). Activation of

GABAB receptor via G-protein can also reduce Ca2þ

conductance and inhibit adenylyl cyclase (Bormann,

1988; Smith et al., 2000). Functional GABAB receptors

are heterodimers of GABABR1 subunit and GABABR2

subunit. This heterodimerization is important in receptor

folding and transport to the cell surface and is also neces-

sary for agonist binding to GABAB receptors (Jones

et al., 1998; White et al., 1998).

GABA-mediated inhibition in the striatum arises

from axon collaterals of spiny projection neurons

(Parent and Hazrati, 1995a; Wu et al., 2000; Tunstall

et al., 2002), GABAergic interneurons (Bolam et al.,

2000; Cicchetti et al., 2000), GPe (Kita et al., 1999)

and SNr (Hanley and Bolam, 1997). Activation of spiny

neurons rarely triggers synaptic transmission in other

nearby neurons (Tunstall et al., 2002) whereas action

TR

potentials evoked by interneurons are capable of produ-

cing stronger GABA-mediated synaptic transmission in

spiny neurons (Koos and Tepper, 1999). Hence, it was

suggested that most of the strong inhibition of medium

spiny neurons is principally controlled by GABAergic

interneurons even though there are many times more

collateral synapses with medium spiny neurons than

interneurons (Kita, 1993; Tepper et al., 2004).

A recent study reports that dopamine plays a critical

role in the modulation of striatal interneurons activity

through postsynaptic dopamine D5 receptors and presy-

naptic dopamine D2 receptors located on GABAergic

nerve terminals (Centonze et al., 2003b). This

study demonstrates that both isoforms of dopamine D2

receptors, D2L and D2S, are involved in the presynaptic

inhibition of dopamine on GABA transmission. More

recently, it has been demonstrated that GABAA receptor

stimulation is able to rescue the locomotor deficits of

the dopamine D2 R�/� mice, suggesting that this recep-

tor interacts with GABAA receptors to control the motor

circuits in the BG (An et al., 2004). In addition, the

dopamine D5 receptor physically interacts with the

ionotropic GABAA receptor. In cells coexpressing the

two receptors, the D5-mediated stimulation of adenylyl

cyclase was inhibited by GABAA, while the GABA-

induced chloride current was decreased by the activa-

tion of the dopamine receptor, indicating reciprocal

receptor cross-talk (Liu et al., 2000).

The inhibitory postsynaptic potential induced by the

collateral of the medium spiny neurons could attenuate

or block the transient effects of nearby corticostriatal

or thalamostriatal excitatory postsynaptic potentials.

Therefore, these axon collaterals, by attenuating gluta-

mate-mediated excitatory postsynaptic potentials, may

play an important role in Ca2þ-dependent changes in

the synaptic efficacy of corticostriatal or thalamostriatal

synapses. It seems that GABAB receptors are involved

in the presynaptic regulation of glutamate release

(Calabresi et al., 1991, 2000a; Tepper et al., 2004).

Activation of GABAA receptors by synaptically

released GABA causes a fast membrane depolarization

in striatal neurons via chloride conductance. The

synaptic depolarizing effect of this inhibitory transmit-

ter is due to the high resting potential of medium spiny

neurons (–80 mV) (Calabresi et al., 2000a). In addi-

tion, synaptically released GABA exerts a feedback

control on its own release in the striatum via presynap-

tic GABAB receptors and it may also be able to reduce

GABA-mediated depolarizing synaptic potentials

(Calabresi et al., 1991). Accordingly, it was suggested

that feedback inhibition by axon collaterals also plays

a significant role in the information-processing opera-

tion of the striatum (Tunstall et al., 2002). However,

the functional role of this feedback inhibition by axon


collaterals in the striatum is complex and remains to

be better clarified (Tepper et al., 2004).


2.5.2.1. GABAA receptors in the BG

The distribution of GABAA receptors in the BG of

human and monkey in normal and parkinsonian condi-

tions has been reported using benzodiazepine-binding

studies with GABAA receptor. These studies demon-

strated that GABAA/benzodiazepine receptors are dis-

tributed in caudate and putamen according to the

patch and matrix compartments (Waldvogel et al.,

1998, 1999). In human BG, GABAA receptors are

found in highest concentrations on the GABAergic

interneurons of the striatum and on the output neurons

of the globus pallidus and SNr (Waldvogel et al.,

2004). It has been suggested that presynaptic GABAA

receptors in the globus pallidus may be involved in the

modulation of release of GABA (Waldvogel et al.,

1998; Smith et al., 2001). In 1-methyl-4-phenyl-1,2,3,6-

tetrahydropyridine (MPTP) parkinsonian monkeys, the

density of GABAA/benzodiazepine-binding sites is

decreased in the medial anterior part of the caudate and

putamen and it remains unchanged after treatment with

pulsatile or continuous dopamine D1 receptor agonist

(Calon et al., 1999). In dorsal striatum, GABAA/benzo-

diazepine-binding sites remained reduced in parkinsonian

monkeys treated with long-acting dopamine D2 receptor

agonist, but was not significantly lower than untreated

MPTP monkeys (Calon et al., 1999). The effects of the

GABAA receptor are suggested to be postsynaptic and

are thought to be mediated by striatal interneurons con-

taining parvalbumin (Koos and Tepper, 1999) or by a

striatonigral feedback loop (Smolders et al., 1995).

The density of GABAA/benzodiazepine-binding

sites in the globus pallidus is lower than in the striatum

and is more important in GPe than in GPi (Waldvogel

et al., 1998, 1999). After MPTP treatment in the pri-

mate animal model of PD, the density of GABAA/ben-

zodiazepine-binding sites is increased and decreased,

respectively, in GPi and GPe (Robertson et al., 1990;

Calon et al., 1995, 1999). The current model of BG

circuitry is consistent with the hypoactivity of the

striatonigral and hyperactivity of striatopallidal path-

ways after degeneration of dopaminergic nigrostriatal

neurons in PD. Interestingly, cabergoline, the long-

acting dopamine D2 agonist, but not SKF 82958, the

dopamine D1 agonist, could reverse the increased level

of GABAA/benzodiazepine-binding in GPi of MPTP

monkeys (Calon et al., 1999). The pattern of GABAA

receptor expression in the SNr is similar to that in the

GPi and treatment with MPTP in monkeys increases

the level of GABAA/benzodiazepine-binding sites in

the SNr (Smith et al., 2001).

DI

STN neurons also demonstrate strong immunoreac-

tivity for GABAA receptor subunits in rats and mon-

keys (Smith et al., 2001). Indeed, infusion of the

GABAA receptor agonist, muscimol, into the STN

has a beneficial effect in the symptomatic relief in

patients with advanced PD (Levy et al., 2001).

32 P. SAMA

2.5.2.2. GABAB receptors in the BG

GABAB receptors are expressed by most neurons in

the BG. Both the R1 and R2 subunits of the GABAB

are distributed throughout the monkey and human stria-

tum. Most striatal interneurons containing parvalbumin

or calretinin, 50% of those containing neuropeptide Y

and 80% of cholinergic interneurons express GABAB

receptor and generally these interneurons are more

strongly labeled than medium spiny neurons (Charara

et al., 2000; Waldvogel et al., 2004). These GABAB

receptors are located at a presynaptic location to med-

ium spiny neurons either on GABAergic terminals or

on GABAergic interneurons (Nisenbaum et al., 1993;

Waldvogel et al., 2004). In addition GABAB receptors

are also located on glutamatergic terminals in the stria-

tum and it has been suggested that these presynaptic

GABAB receptors could modulate the release of gluta-

mate and dopamine (Nisenbaum et al., 1992, 1993;

Smith et al., 2000; Waldvogel et al., 2004). In monkeys,

following treatment with MPTP and dopaminergic

agents, no changes in the density of GABAB receptors

were seen in the striatum (Calon et al., 2000c).

GABAB R1 and GABAB R2 are also localized over

90% of the neurons of the globus pallidus, SNr and

SNc (Waldvogel et al., 2004). In the substantia nigra,

dopaminergic neurons in the SNc were more intensely

labeled for GABAB receptors than GABAergic neu-

rons in the SNr (Charara et al., 2000) and it has been

shown that the release of dopamine is modulated by

GABA receptors (Waldvogel et al., 2004). Moreover,

in MPTP monkeys a significant decrease in GABAB

receptors is seen in SNc, suggesting that SNc neurons

express GABAB receptors, whereas no change is seen

in the SNr of these parkinsonian monkeys (Calon

et al., 2000c). There is also evidence that GABAB

receptors can control the release of glutamate as well

as GABA in the SNr (Shen and Johnson, 1997). In

the globus pallidus, the postsynaptic GABAB receptors

may also be involved in modulating synaptic transmis-

sion in addition to the GABAA-mediated inhibitory

effect (Smith et al., 2000). Furthermore, localization

of the presynaptic GABAB receptors in GPe and GPi

has been demonstrated (Smith et al., 2000). Consistent

with these morphological results, functional studies

showed that activation of GABAB receptors in the

globus pallidus reduces the release of GABA and glu-

tamate by activating presynaptic auto- and hetero-

receptors and hyperpolarizes pallidal neurons by

activating postsynaptic receptors (Chen et al., 2002,

2004a). In MPTP parkinsonian monkeys, the level of

GABAB receptors is significantly increased in the

GPi. However, no changes have been seen in the

GPe (Calon et al., 2000c).

GABAB receptors are also expressed by subthala-

mic terminals and glutamatergic afferents to STN neu-

rons (Charara et al., 2000; Galvan et al., 2004). It is

thought that GABAB receptor stimulation could modu-

late the postsynaptic response to glutamate through

presynaptic receptors (Chen et al., 2004a). In addition,

GABAB receptors may control the activity of STN

neurons by presynaptic inhibition of neurotransmitter

release from extrinsic and/or intrinsic glutamatergic

terminals (Smith et al., 2001). Electrophysiological

studies demonstrated that GABAB receptors modulate

glutamate release in the STN (Shen and Johnson,

2001). Therefore, therapeutic agents such as GABAB

receptor agonists could have beneficial effects in PD

by attenuating the hyperactivity of STN neurons.

Indeed, the application of baclofen was found to

decrease the evoked synaptic currents mediated by

glutamate in the SNr (Shen and Johnson, 1997).

Because GABAB R1 and GABAB R2 need to dimer-

ize to form a functional receptor, it is expected that

these two subtypes display a similar pattern of distribu-

tion. Recent studies in the primate BG demonstrate that

the distribution of GABAB R2 is largely consistent with

that of GABAB R1. However, there are some excep-

tions. For example, low expression levels of GABAB

R2 compared with GABAB R1 are found in the stria-

tum, or a larger proportion of presynaptic elements

labeled for GABAB R1 than GABAB R2 are found in

the globus pallidus and substantia nigra. This raises

the hypothesis that other mechanisms may relay the for-

mation of functional GABAB receptors in specific

regions of BG (Charara et al., 2004).

2.6. Acetylcholine

Striatal cholinergic interneurons, also called tonically

active neurons, fire tonically and do not exhibit long

periods of silence (Zhou et al., 2002). These neurons

are indispensable in controlling striatal neuronal activ-

ity and extrapyramidal motor movement. Evidence

indicates that the imbalance between dopaminergic

and cholinergic systems is one of the neurochemical

bases that play a fundamental role for movement

abnormalities observed in PD (Di Chiara et al., 1994;

Kaneko et al., 2000; Saka et al., 2002).

The almost exclusive source of acetylcholine in the

striatum originates from interneurons (Parent et al.,

ET AL.

TR

1995b). Nevertheless, a large proportion of BG neu-

rons appear to receive a prominent cholinergic input

from the upper-brainstem neurons (Parent et al.,

1995b). The cholinergic interneurons, which account

for <2% of the entire striatal neuronal population,

are distinguished from the medium spiny neurons by

their large somata and extensive dendritic and axonal

arbors. Moreover, the density of cholinergic varicos-

ities is high (Izzo and Bolam, 1988; Smith and Bolam,

1990a; Contant et al., 1996). Furthermore, the high

and precisely overlapping distribution of acetylcho-

line, dopamine, tyrosine hydroxylase and enzymes

involved in the synthesis and degradation of acetylcho-

line in the striatum ensure that the cholinergic and

dopaminergic systems are positioned to interact within

this structure (Zhou et al., 2001). These anatomical

characteristics suggest that these interneurons may be

important for integrating diverse synaptic inputs and

they exert a strong and direct influence on BG output

structures (Calabresi et al., 2000b; Kaneko et al.,

2000; Ragozzino, 2003).

2.6.1. Acetylcholine synthesis, transport and

degradation

Acetylcholine is synthesized in nerve terminals from

its precursor choline and acetylcoenzyme A. Choline

used in acetylcholine synthesis is thought to come

from two sources: the main source is derived from

metabolization of acetylcholine by acetylcholine ester-

ase and the other source is the breakdown of phospha-

tidylcholine, which may be stimulated by locally

released acetylcholine (Webster, 2001a). Choline is

then taken up into the cholinergic neurons by a high-

affinity Naþ-dependent choline uptake system (Taylor

and Brown, 1999; Webster, 2001a). The choline levels

in the brain and plasma seem to be relatively stable at

5–10 mM (Lockman and Allen, 2002). The reaction of

choline with mitochondrial-bound acetylcoenzyme A

is catalyzed by the cytoplasmic enzyme choline acetyl-

transferase (ChAT) present in the presynaptic terminal

of cholinergic neurons (Webster, 2001a; Sarter and

Parikh, 2005). ChAT itself is synthesized in the rough

endoplasmic reticulum of the cell body and transported

to the axon terminal. The rate of acetylcholine synth-

esis is controlled by the capacity of choline transporter

to transport choline into presynaptic terminals

(Lockman and Allen, 2002; Sarter and Parikh, 2005).

Moreover, the choline transporter is also highly regu-

lated and the cellular mechanisms that modulate its

capacity show considerable plasticity. Choline trans-

porters are localized predominantly onto synaptic vesi-

cles that are immunopositive for the vesicular

acetylcholine transporter (VAChT). VAChT transports


acetylcholine into storage vesicles following its synth-

esis. Interestingly, the gene encoding the vesicular

transporter is located within an intron of the ChAT

gene, suggesting a mechanism for co-regulation of

gene expression for ChAT and VAChT. Acetylcholine

uptake in the vesicle is driven by a proton-pumping

ATPase (Hþ exchange) (Taylor and Brown, 1999;

Webster, 2001a). In response to an action potential,

acetylcholine is released by exocytosis into the synaptic

cleft and could act on two distinct receptors. Acetylcho-

line is metabolized by membrane-bound acetylcholine

esterase, also called true or specific cholinesterase to

distinguish it from butyrylcholinesterase, a pseudo- or

non-specific plasma cholinesterase (Webster, 2001a).

The summary of the synthesis, transport and degrada-

tion of acetylcholine is illustrated in Fig. 2.5.


The actions of acetylcholine are the results of fast or

slow synaptic transmission mediated by nicotinic and

muscarinic receptors, respectively.


2.6.2.1. Nicotinic acetylcholine receptors

Nicotinic acetylcholine receptors (nAChRs) consist of

transmembrane proteins and are members of a super-

family of ligand-gated ion channels (Karlin and Aka-

bas, 1995). nAChRs are constituted by five spanning

subunits forming a cylinder-like structure in the mem-

brane around the central ion channel which is perme-

able to Naþ, Kþ and Ca2þ (Taylor and Brown, 1999;

Webster, 2001a). Neuronal nAChRs are composed of

a and b subunits. Five types of a subunits (a2–a6)and three types of b subunit (b2–b4) constitute a- andb-type heteromeric nAChRs, whereas a7 subunits con-stitute homomeric nAChRs. Multiple receptor sub-

types are localized in the striatum and substantia

nigra, including a4b2, a6b2, a4a6b2 and others. How-

ever, a6 receptor subtypes are selectively localized to

the nigrostriatal pathway (Quik, 2004).

nAChRs are located mainly presynaptically, modu-

lating synaptic activity by regulation of neurotransmit-

ter release (Wonnacott, 1997; MacDermott et al.,

1999; Zhou et al., 2001). a7nAChR is expressed at glu-

tamatergic terminals in the striatum (Nomikos et al.,

2000) and its activation stimulates the release of gluta-

mate from corticostriatal terminals (Marchi et al.,

2002). Glutamate, through the activation of ionotropic

GluRs at dopaminergic terminals, could stimulate

dopamine release. Other subtypes of nAChR could

also directly modulate dopamine release from nigros-

triatal dopaminergic terminals (Hamada et al., 2004).

Moreover, electrophysiological studies indicate the

ACh

AChVAChT

Presynapticacetylcholinergic terminal

Choline

Choline

AChE

Acetic acid

ACh CoA

Ac-CoA

ChATChAT

Fig. 2.5. Schematic representation of biosynthesis, release, transport and degradation of acetylcholine in acetylcholinergic

nerve terminals. ACh, acetylcholine; ChAT, choline acetyltransferase; CoA, coenzyme A; Ac-CoA, acetylcoenzyme A; AchE,

acetylcholine esterase; VAChT, vesicular acetylcholine transporter.

34 P. SAMADI ET AL.

presence of nAChRs on the striatal GABAergic inter-

neurons. It was hypothesized that activation of these

nAChRs could reduce the inhibitory effect of striatal

projection neurons and cause some disinhibition of

output nuclei of the BG (Zhou et al., 2003).

Nicotine at low concentrations mainly activates, at

dopaminergic terminals, high-affinity b2-containingnAChRs with rapid desensitization properties (Picciotto,

2003; Hamada et al., 2004). However, nicotine at high

concentration could activate both high-affinity and

low-affinity (a7) nAChRs in the striatum. This latter,

localized at glutamatergic terminals, is less susceptible

to desensitization and their activation results in longer-

lasting actions of nicotine (Hamada et al., 2004).

Furthermore, it has been shown that nicotine at these

low and high concentrations by activation of dopamine

D2 and D1 receptors might differentially regulate

the state of phosphorylation of DARPP-32 at Thr-34

(Hamada et al., 2004). These differential effects of

nicotine in the two major outputs of the striatum could

contribute to a better understanding of the modulatory

effect of the cholinergic system in PD.

In PD, most reports indicate a reduction in nicotine

binding in caudate and putamen in parallel with the

decline in dopaminergic markers (Court et al., 2000a,

b; Quik and Kulak, 2002; Pimlott et al., 2004). More-

over, reduced nicotine binding has also been demon-

strated in the substantia nigra in PD, highlighting the

loss of dopaminergic neurons projecting to the striatum

(Perry et al., 1995; Pimlott et al., 2004). Studies in ani-

mal models of PD also show that a decline in nAChRs

is paralleled by a decrease in nicotine-evoked dopamine

release (Quik et al., 2003b). Accordingly, it was sug-

gested that drugs targeting the subtypes of nAChR that

decline with nigrostriatal degeneration might be useful

in treating PD (Quik, 2004). Additionally, co-

administration of an nAChR agonist with a low dose

of levodopa improves parkinsonian syndrome similar

to a high dose of levodopa, while the involuntary move-

ments are reduced (Schneider et al., 1998). Levodopa

treatment has been reported to decrease nAChR expres-

sion in unlesioned animals, but not in animals with

severe nigrostriatal damage, suggesting that levodopa

affects nAChRs associated with dopaminergic terminals

(Quik et al., 2003a). This effect may be relevant to the

reduction of the effectiveness of levodopa with time in

parkinsonian patients (Quik et al., 2003a). Furthermore,

it has been reported that acetylcholine, through both

nicotinic and muscarinic receptor activation, may regu-

late striatal dopaminergic transmission, in part by mod-

ulating DAT availability (Tsukada et al., 2001). The

effects of nAChR activation on dopamine transport

function appear to be mediated in part through PKC

(Gulley and Zahniser, 2003).

Some evidence also suggests that nicotine has a neu-

roprotective efficacy against nigrostriatal damage in the

TR

long term. This effect could result from nicotine-evoked

dopamine release, which competes with toxins for entry

into neurons via the same uptake system (Di Monte,

2003; Quik, 2004). The neuroprotective effect of nico-

tine could also be through a variety of neuronal

mechanisms ranging from the inhibition of apoptosis

and/or production of growth factors such as fibroblast

growth factor (Belluardo et al., 2000; Roceri et al.,

2001), reduction of superoxide anion generation in

brain mitochondria (Cormier et al., 2003) and antioxi-

dant action (Newman et al., 2002). More recently, it

was reported that a nicotine neuroprotection effect

might result from negative regulation of microglia acti-

vation through a7nAChRs (Shytle et al., 2004).


2.6.2.2. Muscarinic acetylcholine receptors

Muscarinic acetylcholine receptors (mAChRs) belong

to the seven transmembrane G-protein coupled receptor

family. Molecular cloning has identified five distinct

mAChRs: M1–M5 (Caulfield and Birdsall, 1998). M1,

M3 and M5 receptors, also called M1-like mAChRs,

couple to similar G-proteins (Gq family) that activate

phospholipases and metabolize intracellular Ca2þ (Zhou

et al., 2003). M2 and M4 receptors, also called M2-like

mAChRs, by coupling to G-proteins of the Gi/Go

family, can inhibit adenylyl cyclase and reduce the level

of cAMP and neuronal activity by inhibiting different

classes of Ca2þ channels (Zhou et al., 2003). Striatal

medium spiny neurons express primarily M1 and M4

mAChRs. The main population of M1 receptors is

expressed with striatopallidal neurons that also express

dopamine D2 receptors (Ince et al., 1997; Kayadjanian

et al., 1999) while M4 receptors and dopamine D1 recep-

tors are coexpressed on striatonigral neurons (Ince et al.,

1997; Bernard et al., 1999; Santiago and Potter, 2001).

The coexpression of dopamine D1 receptors with M4

mAChRs on striatal medium spiny neurons and their

opposing action on cAMP formation may have a regula-

tory action on medium spiny neurons (Zhou et al., 2003).

The M2 and M4 receptors are also present on the soma-

todendritic areas and the axon terminals of striatal choli-

nergic interneurons (Bernard et al., 1998). The presence

of muscarinic receptors on striatal afferents has also been

reported, for example, M5 receptor mRNA is detectable

in dopaminergic neurons of SNc, suggesting that M5

receptors are located on dopaminergic nerve terminals

(Zhang et al., 2002b). M3 receptor is expressed at a

low level in a subset of GABAergic nerve terminals in

the striatum (Zhang et al., 2002b).

Acetylcholine could regulate the release of dopamine,

GABA and glutamate in the striatum via presynaptic

mechanisms (Sugita et al., 1991). Recently, it has been

shown that mAChRs are involved in the regulation of

striatal dopamine release. M3 receptors located on

GABAergic nerve terminals inhibit dopamine release

by stimulating GABA release, whereas activation of

M4 and M5 receptors facilitates this release (Zhang

et al., 2002b). While the M4 and M2 mAChRs are

involved in the autoinhibition of striatal acetylcholine

release (Zhang et al., 2002a) presynaptic M1 or M1/M2

receptors have been reported to reduce GABAergic

inputs in the striatum (Calabresi et al., 2000b). More-

over, activation of presynaptic M2 receptors could

reduce the release of glutamate from corticostriatal

neurons (Calabresi et al., 2000b). Both striatal medium

spiny neurons and cholinergic interneurons receive glu-

tamatergic inputs from cortex and thalamus. The fact

that striatal projection neurons are the main target of

cholinergic interneurons suggests that these interneurons

mediate the processing input from the cortex to the med-

ium spiny neurons (Calabresi et al., 2000b).

It was suggested that M1 receptors located at postsy-

naptic sites on medium spiny neurons might modulate

postsynaptic glutamate receptors. Indeed, activation of

cholinergic transmission in the striatum has been shown

to influence LTP at corticostriatal synapses (Calabresi

et al., 1998, 2000b). The M1-like mAChR antagonist

pirenzepine blocks the induction of striatal LTP,

whereas it is significantly enhanced by methoctramine

(Calabresi et al., 1999a). Accordingly, activation of

mAChRs in the striatum influences corticostriatal

synaptic plasticity and may facilitate long-term changes

in striatal output patterns that enable the shifting of

behavioral strategies (Ragozzino, 2003).

Striatal acetylcholine release is under a complex reg-

ulation involving dopaminergic, glutamatergic and

GABAergic inputs (Koos and Tepper, 2002). Activation

of dopamine D5 receptor, expressed on all cholinergic

interneurons (Rivera et al., 2002a), could depolarize

these interneurons while activation of dopamine D2

receptors inhibits acetylcholine release (Centonze

et al., 2003b; Zhou et al., 2003). Indeed, in neurolep-

tic-induced parkinsonism, since dopamine D2 receptors

are blocked, dopamine excitation of cholinergic inter-

neurons could increase acetylcholine release (Zhou

et al., 2003). This potential mechanism may, in part,

explain the efficacy of antimuscarinic drugs in parkin-

sonism induced by neuroleptic (Zhou et al., 2003).

The mGlu2 receptors are also expressed on cholinergic

interneurons and their activation, interfering with N-

type Ca2þ channel, reduces the activity of cholinergic

interneurons and could lead to a decreased acetylcho-

line release in the striatum (Pisani et al., 2002, 2003).

According to the hyperactivity of cholinergic interneur-

ons in PD and dopamine and glutamate modulation of

synaptic plasticity in the striatal cholinergic interneur-

ons, careful management of these interneurons may be


DI

helpful in the treatment of PD. Indeed, pharmacological

enhancement of muscarinic receptors can induce a par-

kinsonian syndrome, whereas antimuscarinic drugs pre-

sented one of the earliest therapies in PD (Carlsson,

2002).

The recognition that striatal cholinergic interneur-

ons play a significant role in BG circuitry by modify-

ing the excitability of striatal output neurons could

present an alternative intervention for drug develop-

ments targeting AchRs in the treatment of PD.

2.7. Serotonin (5-HT)

Serotonergic afferents to the BG principally originate

from the dorsal raphe nuclei (Parent, 1996). Although

all the core structures of the BG in primates receive a

significant serotonergic input, the densities and patterns

of innervation vary markedly from one structure to

another (Lavoie and Parent, 1990). The dorsal raphe–

striatal projection is mainly ipsilateral and arborizes pro-

fusely within the entire caudate–putamen complex, but

slightly more heavily in the ventrocaudal region (Lavoie

and Parent, 1990; Parent, 1996). Surprisingly, only 10–

15% of 5-HT varicosities exhibit a typical synaptic

junction in the striatum of rats (Arluison and De La

Manche, 1980; Soghomonian et al., 1989). This sug-

gests that the effects of 5-HT in the striatum are exerted

on a multiplicity of cellular target sites in addition to the

restricted number of dendritic spines and shaft synapti-

cally contacted by 5-HT terminals. Interestingly, dorsal

raphe neurons projecting to the striatum also send axon

collaterals to the substantia nigra. The 5-HT afferent

input from the dorsal raphe nucleus to midbrain dopa-

mine neurons is one of the most prominent (Dray

et al., 1976; Fibiger and Miller, 1977; Wirtshafter

et al., 1987; Lavoie and Parent, 1990; Vertes, 1991).

In summary, anatomical data on the 5-HT connectivity

within BG indicate that 5-HT is in a position to modu-

late BG function by interacting with dopamine systems

both at the level of substantia nigra where dopamine

neurons are found and at the level of their main target

structure, i.e. the striatum. It is thus likely that 5-HT

receptors play a role in regulating the appropriate selec-

tion of voluntary movement by the BG, and abnormal-

ities in 5-HT transmission may contribute to the

neural mechanisms of PD and complications associated

with long-term treatment with levodopa (Hornykiewicz,

1998; Nicholson and Brotchie, 2002).

2.7.1. Serotonin biosynthesis, transport, release

and degradation

The neurotransmitter 5-HT is synthesized from the

amino acid tryptophan in two biochemical steps. The

36 P. SAMA

primary source of tryptophan is dietary protein. The

entry of tryptophan into brain is not only related to

its concentration in blood, but is also a function of

its concentration in relation to the concentrations

of other neutral amino acids. The initial step in the

synthesis of 5-HT is the conversion of l-tryptophan to

5-hydroxytryptophan (5-HTP) by the enzyme trypto-

phan hydroxylase. This enzyme is only found in brain

cells that synthesize 5-HT (serotonergic neurons); its

distribution in brain is similar to that of 5-HT itself.

The conversion of tryptophan to 5-HTP is the rate-limit-

ing step in the 5-HT metabolic pathway. Therefore,

inhibition of this initial step by an enzyme inhibitor

such as para-chlorophenylalanine results in a marked

and long-lasting depletion of the content of 5-HT in

brain. The second enzyme involved in the synthesis of

5-HT is AADC, which converts 5-HTP to 5-HT. This

second enzyme, AADC, is the same for both catechola-

mines and 5-HT. Under appropriate conditions, the

synthesis of brain 5-HT in rats can be enhanced by

the consumption of a high-carbohydrate, low-protein

meal. Administration of an amino acid mixture lacking

tryptophan has been used to deplete 5-HT temporarily

in human studies (Frazer and Hensler, 1993; Meyer

and Quenzer, 2005).

As with other biogenic amine transmitters, 5-HT is

stored primarily in vesicles and is released by an exo-

cytotic mechanism. As expected for a classical neuro-

transmitter, 5-HT terminals make the usual specialized

synaptic contacts with target neurons and release 5-HT

following nerve stimulation. However, there are

numerous areas of the mammalian CNS where 5-HT

is released and no evidence for synaptic specialization

can be found. In this case, it is believed that 5-HT can

diffuse over distances as great as several hundred

microns (Jacobs and Amiztia, 1992) and may act as a

neuromodulator, i.e. adjusting or tuning ongoing

synaptic activity. As previously mentioned, a low per-

centage of 5-HT exhibits typical synaptic junctions in

the striatum of rats (Arluison and De La Manche,

1980; Soghomonian et al., 1989), suggesting a diffuse

and less specific effect of 5-HT on striatal neurons.

5-HT is transported into synaptic vesicles using the

same vesicular transporter, VMAT2, found in dopami-

nergic and noradrenergic neurons. As with catechola-

mines, storage of 5-HT in vesicles plays a critical

role in protecting the transmitter from enzymatic

breakdown in the nerve terminal. Consequently, the

VMAT blocker reserpine depletes 5-HT neurons of

5-HT, just as it depletes catecholamines in dopaminer-

gic and noradrenergic neurons (Frazer and Hensler,

1993; Meyer and Quenzer, 2005).

The rate of 5-HT release is dependent on the firing

rate of 5-HT neurons in the raphe nuclei. 5-HT release

ET AL.

TR

is inhibited by the somatodendritic 5-HT1A autorecep-

tors and by presynaptic 5-H1B or 5-HT1D, depending

on the species, located on terminals of 5-HT neurons.

Release of 5-HT can be directly stimulated by a family

of drugs based on the structure of amphetamine. These

compounds include para-chloroamphetamine, fenflur-

amine and the recreational and abused drug 3,4-methy-

lenedioxymethamphetamine (MDMA). Synaptic effects

of 5-HT are terminated by binding of the neurotrans-

mitter molecules to a specific transporter, the 5-HT

transporter (5-HTT) (Frazer and Hensler, 1993; Meyer

and Quenzer, 2005). 5-HTTs are located on 5-HT neu-

rons and terminals. The 5-HTT turns out to be a key

target for drug action. Examples include antidepressant

drugs known as selective serotonin reuptake inhibitors

(SSRIs) and other non-selective drugs such as cocaine

and MDMA that also influence the dopamine transpor-

ter. Glial cells also appear to be able to take up 5-HT

by a high-affinity transport system.

The primary catabolic pathway for 5-HT is oxida-

tive deamination by the enzyme MAO which yields

to the formation of the metabolite 5-hydroxyindoleace-

tic acid. The level of 5-hydroxyindoleacetic acid in the

brains of animals or in the cerebrospinal fluid of

humans or animals is often used as a measure of the

activity of 5-HT neurons (Frazer and Hensler, 1993;

Meyer and Quenzer, 2005).


5-HT neurotransmission is mediated by at least 14

structurally and pharmacologically distinct 5-HT recep-

tor subtypes categorized into seven distinct families

(5-HT1–5-HT7) on the basis of their molecular biology,

signal transduction mechanisms and pharmacology.

Some of these receptor subtypes fall within groups,

such as the large family of 5-HT1 receptors (5-HT1A,

1B, 1D, 1E, 1F) and the smaller 5-HT2 receptor family

(5-HT2A, 2B, 2C). The remaining 5-HT receptor subtypes

are designated as 5-HT3, 5-HT4, 5-HT5A, 5B, 5-HT6 and

5-HT7. All of the 5-HT receptors are metabotropic,

except for the 5-HT3 receptor, which is an excitatory

ionotropic receptor (Barnes and Sharp, 1999).

Many of these 5-HT receptor subtypes are distributed

in low to high density in the BG. Although 5-HT1A

receptors are found in low density in the caudate puta-

men of primates (Frechilla et al., 2001), they may

modulate BG function by an effect outside the BG.

These somotadendritic autoreceptors are located on

neurons of the dorsal raphe that send prominent effer-

ents to the BG and therefore control 5-HT release in

those structures. 5-HT1B sites have predominantly

been found on terminals of 5-HT neurons in the stria-

tum and on GABAergic striatal output neurons in the


globus pallidus and substantia nigra (Maroteaux

et al., 1992; Boschert et al., 1994; Doucet et al.,

1995; Riad et al., 2000), suggesting a role for these

receptors in the modulation of dopamine neurotrans-

mission and GABA release. The 5-HT1E receptor

subtype (McAllister et al., 1992) is also found at high

density in the striatum, where it is thought to be

located postsynaptically (Barone et al., 1993; Barnes

and Sharp, 1999). 5-HT2A and 5-HT2C receptor sub-

types are found in moderate to high densities in the

caudate nucleus and output regions of the BG such

as the globus pallidus and substantia nigra pars reticu-

lata (Barnes and Sharp, 1999). They have been shown

to modulate striatal dopamine release both in vivo and

in vitro (Benloucif and Galloway, 1991; Benloucif

et al., 1993). In rodent models of PD, 5-HT2C receptors

play a key role in controlling BG outputs (Nicholson

and Brotchie, 2002), since antagonists increase loco-

motion and enhance the behavioral response to dopa-

mine agonists (Fox and Brotchie, 2000). The 5-HT4

and 5-HT6 receptor subtypes are positively coupled to

adenylate cyclase and found in high densities in the

caudate nucleus (Barnes and Sharp, 1999), although their

functional role is still unknown.

2.8. Neuropeptides

In addition to the classical neurotransmitters described

above, the BG contains a great diversity of neuroactive

peptides (Graybiel, 1990; Parent et al., 1995b); they

are listed in Table 2.1. Unlike classical neurotransmit-

ters, there is no mechanism for reuptake and recycling

of neuropeptides after receptor activation (Dockray,

1995). Their action is terminated by internalization

and degradation of receptor-bound peptide or mainly

by metabolism by proteolytic enzymes (Konkoy and

Davis, 1996).

Replacement of neuropeptides after release is

dependent on new synthesis in nerve cell body and

axonal transport. This is a relatively slow process com-

pared to classical neurotransmitters that are synthe-

sized locally in nerve terminals and replaced by

reuptake mechanisms. Repeated or prolonged stimula-

tion will therefore more easily exhaust neuropeptide

release.

Many neuropeptides identified in the brain have

their highest concentration in the BG and their related

structures. In the BG the principal site of synthesis is

the striatum (Graybiel, 1986).

Neuropeptides are involved in fast and slow synap-

tic transmission (Graybiel, 1990). They can exert their

biological effects as neurotransmitters, neuromodula-

tors or neurotrophic-like factors (Graybiel, 1990; Chen

et al., 2004b).


DI

The neuropeptides that have been mostly investi-

gated in the BG are the neurokinin peptide SP and

the opioid peptides Enk and Dyn (Parent et al., 1995b).

2.8.1. Neurokinins

Neurokinins are a group of neuropeptides including SP

(or neurokinin-1, NK-1), substance K (SK or neurokinin-

2, NK-2 or neurokinin A) and neuromedin K (NK or neu-

rokinin-3, NK-3 or neurokinin-B) (Chen et al., 2004b).

Their biological functions are mediated by three distinct

receptors, the SP receptor (SPR or NK-1 receptor, NK

or NK-1R), the SK receptor (SKR or NK-2R) and the

NK receptor (NKR or NK-3R), respectively. These

receptors are coupled to Gi proteins and modulate

intracellular signaling cascades such as adenylate

cyclase, calcium and potassium channel activity (Chen

et al., 2004b). Pharmacological studies indicate that SP,

neurokinin-A and neurokinin-B preferentially interact

with NK-1R, NK-2R and NK-3R, respectively (Arenas

et al., 1991; Glowinski and Beaujouan, 1993; Khawaja

and Rogers, 1996; Chen et al., 2004b).

The neurokinins SP, neurokinin-A and neurokinin-

B possess a common carboxy-terminal sequence Phe-

X-Leu-Met-NH2 that accounts for their biological

properties (Chen et al., 2004b). The neurokinins are

synthesized from the expression of the preprotachyki-

nin genes A and B (PPT-A gene and PPT-B gene).

The PPT-A gene generates alpha-, beta- and gamma-

PPT-A mRNAs whereas the PPT-B gene generates

PPT-B mRNA. SP is produced from alpha-, beta- or

gamma-PPT-A mRNAs whereas neurokinin-A is pro-

duced from beta- or gamma-PPT-A mRNAs and neu-

rokinin-B from PPT-B mRNA (Chen et al., 2004b).

SP is the most abundant in the CNS, followed by

neurokinin-A and neurokinin-B. They are abundant

in the BG and their molar ratio is relatively constant

in the striatum–substantia nigra system. The distribu-

tion of these neurokinins and their receptors is well

documented by binding, in situ hybridization and

immunocytochemical studies (Chen et al., 2004b). In

the rat caudate putamen and substantia nigra the three

neurokinins were found concentrated in the synaptoso-

mal fraction and in fractions containing heavy synaptic

vesicles (Diez-Guerra et al., 1988). This localization in

vesicles is consistent with a role of neurotransmitter

and neuromodulator for neurokinins. In situ hybridiza-

tion and immunohistochemistry further confirmed the

localization of all three neurokinins in the striatum,

globus pallidus and substantia nigra (Inagaki and Par-

ent, 1984; Bolam et al., 1986; Hokfelt et al., 1991;

Manley et al., 1994; Lee et al., 1997; Chen et al.,

2004b). The spiny neurons of the direct output path-

way of the striatum express SP, Dyn and dopamine

38 P. SAMA

D1 receptors, whereas spiny neurons of the indirect

pathway express Enk and D2 receptors (Fig. 2.1). SP

is important in mediating the functions of the direct

striatonigral pathway (Emson et al., 1977; Jessell

et al., 1978; Chen et al., 2004b).

In situ hybridization and immunohistochemical stu-

dies also show the abundant distribution of neurokinin

receptors in the BG of mammals mostly localized to

neuronal cell bodies and dendrites (Chen et al.,

2004b). Double-labeling methods have shown that

neurons of the neostriatum and the substantia nigra

display distinct subclasses of neurokinin receptors

(Chen et al., 2004b). About two-thirds of substantia

dopamine neurons are found to display NK-3R but

not NK-1R immunoreactivity, whereas in the neostria-

tum NK-1R immunoreactivity is found (Chen et al.,

1998). In the neostriatum, NK-1R immunoreactivity

was detected in large and medium-sized aspiny neu-

rons and virtually all NR-1R-immunoreactive neurons

contained ChAT or somatostatin (Kaneko et al.,

1993, 2000). These results suggest that different neu-

rokinins and their receptors have distinct functional

roles in the BG. The distribution of SP and its receptor

SPR does not match in some brain regions (Shults

et al., 1984; Nakaya et al., 1994). This has been

explained by the fact that, in contrast to more ‘clas-

sical’ synapses, where the receptor immediately

apposes the site of neurotransmitter storage and

release, much of the surface of SPR-expressing neu-

rons can be targeted by SP that diffuses a considerable

distance from its site of release (Chen et al., 2004b).

Numerous studies show that neurokinins affect the

physiology of neurons in the BG. They are involved

in the firing and neurotransmitter release of striatal

and substantia nigra neurons (Otsuka and Yoshioka,

1993; Khawaja and Rogers, 1996; Chen et al.,

2004b). NK-1, NK-2 and NK-3 receptor activation

by specific agonists are shown to increase striatal

dopamine and acetylcholine release (Glowinski et al.,

1993). Furthermore, 5-HT metabolism is shown to be

increased with SP and a selective NK-3 ligand (Humpel

et al., 1991; Humpel and Saria, 1993). Neurokinins

were also shown to play a role in the neuroprotection

of dopamine neurons. There is evidence that neuroki-

nins may play a role in neuroprotection of neurons

through antiglutamate excitotoxicity (Arenas et al.,

1993; Sanberg et al., 1993; Wenk et al., 1995, 1997;

Calvo et al., 1996; Chen et al., 2004b). Furthermore,

neurokinins have been suggested to have activity to

promote neuronal cell growth that is analogous to

neurotrophic factors (Barker, 1986, 1991, 1996;

Iwasaki et al., 1989; Barker and Larner, 1992; Barker

et al., 1993). A decrease of SP and SPR is observed

in the striatum and substantia nigra of postmortem

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TR

PD brains (Tenovuo et al., 1984, 1990; Levy et al.,

1995b). This decrease is also observed in 6-OHDA rats

and MPTP-lesioned monkeys (Arai et al., 1987; Perez-

Otano et al., 1992).

2.8.2. Endorphins

Endogenous opioids or endorphins form a complex

family generated from three genes encoding precursors

(Akil et al., 1998). The first to be characterized was

proopiomelanocortin, the common protein precursor

for b-endorphin as well as the stress hormone adreno-

corticotropic hormone (Nakanishi et al., 1979). The

other two opioid precursors are proenkephalin and pro-

dynorphin. Proenkephalin encodes multiple copies of

Met-enkephalin, a heptapeptide and octapeptide, and

one copy of Leu-enkephalin. Prodynorphin encodes

three opioid peptides of various lengths that all begin

with the Leu-enkephalin sequence: dynorphin-A,

dynorphin-B and neo-endorphin (Akil et al., 1998).

There are three major classes of opioid receptors: m,k and d. All three receptors belong to the superfamily

of G-protein-coupled receptors and share significant

sequence homology, with 61% identity at the amino

acid level (Akil et al., 1998). All three opioid receptors

inhibit adenylate cyclase. An orderly pattern of asso-

ciation between the three families of endogenous

ligands and the three opiate receptors is not observed.

Although proenkephalin products are generally asso-

ciated with d receptors and prodynorphin with kreceptors, a fair amount of ‘cross-talk’ exists (Mansour

et al., 1995). The k-receptor exhibits the greatest

degree of selectivity across endogenous ligands, with

1000-fold more affinity for dynorphin-A (1–7) than

Leu-enkephalin. m and d receptors only have a 10-fold

difference between the least and most preferred

ligands, with a majority of endogenous ligands exhi-

biting greater affinity towards d than m receptors (Akil

et al., 1998). Hence, high-affinity interactions are pos-

sible between each precursor family and each of the

three receptors. The only exception is the lack of high

affinity of proopiomelanocortin peptides for the kreceptor.

The striatum is among the brain regions with the

highest levels of opioid peptides and receptors (Steiner

and Gerfen, 1998). Both direct and indirect striatal

output pathways use the inhibitory neurotransmitter

GABA (Kita and Kitai, 1988), but differ in the neuro-

peptides they express (Fig. 2.1). Striatonigral neurons

generally contain Dyn and SP, whereas striatopallidal

neurons express Enk (Brownstein et al., 1977; Vincent

et al., 1982; Beckstead and Kersey, 1985; Gerfen and

Young, 1988; Reiner and Anderson, 1990; Curran

and Watson, 1995; Le Moine and Bloch, 1995). DA


regulates in opposite direction the expression of neuro-

peptides in the direct and indirect output pathways of

the striatum. For example, dopamine depletion leads

to a decrease in SP and Dyn expression in striatonigral

neurons and an increase in Enk expression (Young

et al., 1986; Voorn et al., 1987; Gerfen et al., 1990,

1991; Li et al., 1990; Engber et al., 1992). This effect

can be reversed, respectively, by D1 agonists for the

striatonigral neurons and by D2 agonists for the striato-

pallidal neurons (Gerfen et al., 1990; Engber et al.,

1992). Consistent with these observations, D1 receptor

knockout mice have decreased expression of SP and

Dyn, whereas D2 receptor knockout mice show mostly

increased expression of Enk (Drago et al., 1994; Xu

et al., 1994; Baik et al., 1995). Postmortem studies in

tissue from patients with idiopathic PD have been gen-

erally less conclusive than those in animal models.

Expression of preproenkephalin (PPE) in the brain of

levodopa-treated PD patients was shown to be either

unaltered (Levy et al., 1995b) or increased in the cau-

date nucleus and the putamen (Nisbet et al., 1995).

Met-enkephalin and SP were found to be subnormal

in PD BG (Fernandez et al., 1996). Studies in human

brains have often not taken into account the develop-

ment of motor complications following levodopa ther-

apy. Indeed, several lines of evidence suggest that

alteration of neuropeptides may be linked to the patho-

genesis of levodopa-induced dyskinesias (Henry and

Brotchie, 1996; Brotchie, 1998; Calon et al., 2000a,

b). In situ hybridization studies in parkinsonian mon-

keys (Morissette et al., 1997) and human PD patients

(Calon et al., 2002) suggest that an increased expres-

sion of PPE mRNA is associated with levodopa-

induced dyskinesias. Increased striatal prodynorphin

(also called preproenkephalin-B) expression was also

observed to be associated with dyskinesias in PD

(Henry et al., 2003). Recent behavioral results pro-

posed that the increased production of opioids in

the two major striatal output pathways might have a

protective role as a compensatory mechanism, which

attempts to attenuate the changes in synaptic transmis-

sion caused by the lack of striatal dopamine as well

as by the abnormal stimulation of dopamine receptors

in PD leading to dyskinesias (Samadi et al., 2003,

2004). Data on Enk and Dyn suggest that both opioid

peptides function, at least in part, as autoregulatory

mechanisms to modulate the pathways they are con-

tained in. The synthesis of both neuropeptides is

upregulated by chronic drug/treatment and/or lesions

that activate these pathways. These changes in gene

regulation are likely adaptive responses in the neurons

in order to restore homeostasis by counteracting

perturbations produced by the drug exposure and/or

lesion.


DI

2.8.3. Neurotensin

Neurotensin (NT) is a tridecapeptide with widespread

distribution in the brain, suggesting that it may

play an important role as a neurotransmitter or neuro-

modulator (Jennes et al., 1982; Zahm et al., 1985).

One species of proneurotensin mRNA exists in the

brain, the product of a single gene which gives

rise to NT and a related peptide neuromedin N

(Kislauskis et al., 1988). Three NT receptors, NTS1,

NTS2 and NTS3, have been cloned to date (Vincent

et al., 1999; Kitabgi, 2002). Most of the known

central effects of NT are mediated through NTS1

(Kitabgi, 2002). NTS1 belongs to the family of G-pro-

tein-coupled receptors with seven transmembrane

domains.

Unlike Dyn and Enk, which are expressed through-

out the caudate putamen at relatively high levels, NT

expression is segregated in dorsomedial and ventrome-

dial subregions of the striatum (White, 1987; Zahm

and Heimer, 1988). Moderate to abundant levels of

NT receptors were observed in the rat striatum,

whereas NT receptor mRNA was not observed (Elde

et al., 1990). This is consistent with lesion studies in

rats suggesting localization of NT-binding sites on

dendrites and axon terminals of nigrostriatal dopami-

nergic neurons (Goedert et al., 1984). In primates the

effect of MPTP on NT-binding sites suggests only par-

tial localization of NT receptors on nigrostriatal dopa-

minergic projections (Goulet et al., 1999). Several

lines of evidence suggest an interaction between NT

and central dopaminergic systems, mainly the nigros-

triatal and mesolimbic DA pathways (Palacios and

Kuhar, 1981; Rostene et al., 1992, 1997; Azzi et al.,

1994; Lambert et al., 1995; Fernandez et al., 1996).

Experimental observations suggest that proneurotensin

mRNA and peptide abundance in the striatum and

accumbens are under tonic inhibitory control by mid-

brain dopaminergic neurons (Angulo and McEwen,

1994). Conversely, neurotensin exerts effects on dopa-

minergic systems of the midbrain and striatum, facili-

tating dopamine release and motor activation in

midbrain and inhibiting amphetamine activation of

motor activity when infused into the accumbens

(Angulo and McEwen, 1994). Depletion of NT recep-

tors in PD and in animal models of this disease has

been reported for the substantia nigra and the striatum

(Sadoul et al., 1984; Uhl et al., 1984; Waters et al.,

1987; Chinaglia et al., 1990; Goulet et al., 1999).

The NT content in the caudate and putamen was

reported to be decreased in the caudate and putamen

(Bissette et al., 1985; Fernandez et al., 1995) of PD

patients and increased in the substantia nigra (Fer-

nandez et al., 1995, 1996).

40 P. SAMA

2.8.4. Other neuropeptides

Other peptides present in the BG, such as neuropeptide

Y, somatostatin, cholecystokinin and angiotensin, are

listed in Table 2.1.

Neuropeptide Y is the most abundant and widely

distributed neuropeptide in mammalian brain (Kask

et al., 2002; Balasubramaniam, 2003). It exhibits a

wide spectrum of central activities mediated by at least

6 G-protein-coupled receptors. Neuropeptide Y and

somatostatin are found in the striatum where they co-

localized in a specific subset of interneurons which

also express NADPH-d (Smith et al., 1985; Smith

and Parent, 1986; Desjardins and Parent, 1992). Neu-

ropeptide Y receptors are also found in moderate to

high concentrations in the striatum (Desjardins and

Parent, 1992). Neuropeptide Y levels are unaltered in

PD (Allen et al., 1985).

The striatum contains the largest number of soma-

tostatinergic neurons in the BG (Johansson et al.,

1984; Chesselet et al., 1995). The actions of somatos-

tatin are mediated by 5 G-protein-coupled receptors

that are widely distributed with high concentrations

in the striatum (Hoyer et al., 1994; Patel, 1999). Soma-

tostatin mRNA is decreased in the striatum after lesion

of the dopaminergic nigrostriatal pathway (Graybiel,

1990; Soghomonian and Chesselet, 1991; Chesselet

et al., 1995). In PD both cerebrospinal fluid and neo-

cortical somatostatin levels have been found to be

decreased, whereas in the BG they remain normal

(Leake and Ferrier, 1993).

The biochemical pathways of the renin–angiotensin

system lead to the formation of angiotensin peptides of

different lengths and the tissue level of octapeptide

angiotensin II is high in the BG (Wright and Harding,

1997). There are three angiotensin receptor subtypes

identified in the mammalian brain (AT1, AT2 and

AT3), the AT2 and AT3 receptors are present in BG

structures such as the caudate putamen, the globus pal-

lidus and the substantia nigra (Wright and Harding,

1997). There is no report of altered angiotensin con-

centrations or its receptors in PD (Graybiel, 1986;

Leake and Ferrier, 1993).

Cholecystokinin levels, a neuropeptide found in the

gut and the brain, are reported to be decreased in the

cerebrospinal fluid and BG but not in the neocortex

of patients with PD (Studler et al., 1982; Verbanck

et al., 1984; Graybiel, 1986; Leake and Ferrier,

1993). Cholecystokinin and dopamine coexist in some

neurons of the ventral midbrain tegmentum and this

peptide has been implicated in dopaminergic regula-

tion (Hokfelt et al., 1980). Two cholecystokinin recep-

tors have been cloned and sequenced in humans

(CCKAR and CCKBR) (Wei and Hemmings, 1999).

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A recent study suggests that the cholecystokinin sys-

tem may influence the development of hallucinations

in PD subjects (Goldman et al., 2004).

Most other neuropeptides (such as corticotropin,

arginine vasopressin, galanin, a-melanocyte-stimulat-

ing hormone, vasoactive intestinal peptide) show mini-

mum changes in either the cerebrospinal fluid or the

brain of patients with PD (Graybiel, 1986; Leake and

Ferrier, 1993).

2.9. Adenosine

Purine and purine nucleotides are present in all cells.

Adenosine, a ‘purinergic messenger’ that regulates

many physiological processes, is released from all

cells, including neurons and glia (Dunwiddie and

Masino, 2001; Ribeiro et al., 2002). In the BG, adeno-

sine interacts closely with dopamine and plays an

important role in the function of striatal GABAergic

efferent neurons (Ferre et al., 2004). The role of ade-

nosine in modulating excitatory glutamatergic trans-

mission is also demonstrated (Ferre et al., 2002;

Domenici et al., 2004). Recently adenosine has

received more attention because its interaction with

dopamine and glutamate could have important impli-

cations for the development of therapeutic strategies

of BG disorders, such as PD.

2.9.1. Synthesis, transport and degradation

Adenosine is neither stored in synaptic vesicles nor

released as a classical neurotransmitter and there is

no evidence for synapses where the primary transmit-

ter is adenosine. Therefore, adenosine belongs to the

group of neuromodulators and influences synaptic

transmission as an extracellular signal molecule

(Ribeiro et al., 2002).

The extracellular adenosine which is produced from

dephosphorylation of adenine nucleotide AMP, by

ecto-50-nucleotidase, is the last step in the catalysis

of extracellular adenine nucleotides such as adenosine

triphosphate. Another potential source of extracellular

adenosine is cAMP. The latter can be released from

neurons and converted into AMP and then adenosine

by phosphodiesterases and ecto-50-nucleotidase, respec-tively (Svenningsson et al., 1999). Finally, the release

of adenosine from cells via transporters is another source

of extracellular adenosine (Lindskog et al., 1999).

Regulation of adenosine levels in the extracellular

space is prominently mediated by facilitated diffusion

nucleoside transporters (Cass et al., 1998). These

transporters are passive and they do not depend on

adenosine triphosphate or ionic gradients to transport

adenosine (Dunwiddie and Masino, 2001). The direc-


tion of the transport (release or reuptake) is dependent

on the gradient concentration of adenosine across cel-

lular membrane. The existence of an active transport

mechanism for adenosine, which depends on the Naþ

gradient to provide energy for transport, has also been

demonstrated; however their role in the regulation of

extracellular adenosine concentration is unclear (Dun-

widdie and Masino, 2001). Adenosine metabolic trans-

formation to inosine by adenosine deaminase is an

alternative pathway for regulating extracellular adeno-

sine concentrations (Dunwiddie and Masino, 2001).

The intracellular production of adenosine is mediated

either via dephosphorylation of AMP by 50-nucleosi-dases or by hydrolysis of S-adenosyl-homocysteine

(Svenningsson et al., 1999). Intracellularly, adenosine

can be converted to AMP by phosphorylation via

adenosine kinase or degraded to inosine by adenosine

deaminase (Lloyd and Fredholm, 1995; Svenningsson

et al., 1999).


Neuromodulatory effects of adenosine are mediated

through activation of four G-protein-coupled receptor

subtypes: the A1, A2A, A2B and A3 receptors (Fred-

holm et al., 2001). The A1 and A3 receptors usually

couple to inhibitory G-proteins (Gi and Go), whereas

A2A and A2B receptors couple to stimulatory G-pro-

teins (Gs) (Ribeiro et al., 2002). Among adenosine

receptors the subtypes A1 and A2A are the main recep-

tors localized in the BG and more precisely in the

striatum (Ferre et al., 1997).

The A1 receptors are highly expressed in the CNS

at both the pre- and postsynaptic sites. These receptors

are present in the striatonigral as well as in striatopal-

lidal GABAergic and corticostriatal glutamatergic

neurons (Ferre et al., 1997). These anatomical locali-

zations indicate that A1 receptors exist in both D1

and D2-containing neurons (Ferre et al., 1997). Activa-

tion of A1 receptor can cause inhibition of adenylyl

cyclase and some voltage-dependent Ca2þ channels,

as well as activation of Kþ channels, phospholipase

C and phospholipase D (Ribeiro et al., 2002). A1

receptor stimulation is linked to inhibition of the neu-

rotransmitter release, most prominently the excitatory

glutamatergic transmission (Dunwiddie and Masino,

2001). In the striatum activation of A1 receptors at

corticostriatal terminals inhibits glutamate release

(Svenningsson et al., 1999). The adenosine A1 receptor

may also control the function of GABAergic inter-

neurons indirectly, by inhibiting their glutamatergic

input, a process relevant during hypoxia (Ribeiro

et al., 2002). Another action of A1 receptors is hyper-

polarization of the resting membrane potential and


DI

reduction of excitability and firing rate (Dunwiddie

and Masino, 2001).

Besides its direct neuromodulatory effects, adenosine

has also receptor–receptor interaction with dopamine in

the CNS, including BG (Franco et al., 2000). Dopamine

via D1 receptor activation increases the activity of A1

receptors by potentiating NMDA-mediated adenosine

release (Harvey and Lacey, 1997). Adenosine A1 and

dopamine D1 receptor interaction may involve the forma-

tion of A1/D1 heterodimers leading to the reduction of

D1 receptors in the high-affinity state or uncoupling

of D1 receptors to the G-protein (Fuxe et al., 1998).

A2A receptors are mainly coupled to Golf, a protein

abundant in the striatum which activates adenylyl

cyclase (Kull et al., 2000). Stimulation of A2A recep-

tors by increasing the activity of this enzyme enhances

the phosphorylation of DARPP-32 at Thr-34 while

decreasing the phosphorylation of DARPP-32 at Thr-

75 (Lindskog et al., 2002). The phosphorylation of

DARPP-32 at Thr-34 and Thr-75 converts this protein

into an inhibitor of PP-1 and of PKA, respectively

(Greengard, 2001). In contrast to A2A agonism, A2A

blockade, by phosphorylation of DARPP-32 at Thr-

75, decreases PKA activation and therefore relieves

the DARPP-32-mediated inhibition of PP-1. PP-1

activity decreases the hyperphosphorylation state of

target proteins, including glutamatergic receptor subu-

nits and transcription factors, such as c-fos, occurring

after dopaminergic denervation in PD (Ribeiro et al.,

2002; Chase et al., 2003; Ferre et al., 2004).

A2A receptors are abundant in the striatum and they

modulate the input and/or output activity of GABAer-

gic medium spiny projection neurons (Hettinger et al.,

2001; Rosin et al., 2003). A2A receptors are mainly

found at postsynaptic sites of striatopallidal GABAer-

gic neurons, which also express dopamine D2 recep-

tors. However, presynaptic and glial A2A receptors

are also present in the striatum (Rosin et al., 2003).

The presynaptic localization of A2A receptors at gluta-

matergic corticostriatal terminals suggests that these

receptors could modulate the glutamatergic cortical

input by stimulating glutamate release (Rosin et al.,

2003). The presence of pre- and postsynaptic A2A

receptors on corticostriatal glutamatergic and striato-

pallidal GABAergic neurons, respectively, suggests

that these receptors may increase the excitability of

medium spiny neurons and, in this manner, play an

important role in the regulation of synaptic plasticity

(Svenningsson and Fredholm, 2003). Presynaptic A2A

receptors located on the terminals of striatal axon col-

laterals (Hettinger et al., 2001) and cholinergic inter-

neurons (Jin et al., 1993) could also modulate

GABAergic and cholinergic inputs to medium spiny

neurons (Rosin et al., 2003; Mori and Shindou, 2003).

42 P. SAMA

Furthermore, A2A receptors are also expressed pre-

synaptically in the GPe at striatopallidal GABAergic

terminals where they may enhance the release of

GABA (Mori and Shindou, 2003; Rosin et al., 2003).

This directly suppresses the excitability of GPe projec-

tion neurons, resulting in disinhibition of STN and its

overactivity, leading to parkinsonian syndrome.

All these results suggest that adenosine transmis-

sion plays an important role in the modulation of

motor function and adenosine A2A antagonists, by

reducing excessive striatopallidal and STN neuronal

activity, could be considered as a novel approach in

PD therapy (Kase, 2001; Chase et al., 2003; Mori

and Shindou, 2003). Accordingly, several behavioral

studies in animal models and in parkinsonian patients

have demonstrated the beneficial effect of A2A recep-

tor antagonism in the treatment of PD and its related

motor complications (Grondin et al., 1999; Kanda

et al., 2000; Morelli and Pinna, 2001; Fredduzzi

et al., 2002; Chase et al., 2003; Calon et al., 2004).

2.9.3. Adenosine and dopamine receptor

heterodimerization

The anatomic localization of dopamine and adenosine

receptor subtypes in striatal projection neurons sup-

ports the existence of functional interactions between

dopamine and adenosine receptors (Franco et al.,

2000). Dopamine D1 and adenosine A1 receptors can

interact with each other to form the heteromer D1/A1.

This heteromerization is essential for the desensitization

and receptor trafficking of D1 receptor agonist-induced

accumulation of cAMP in combined pretreatment with

D1 and A1 receptor agonists. This antagonistic mechan-

ism may contribute to the D1/A1 functional antagonism

found in the brain and offers a basis for the design of a

novel agent to treat PD based on the pharmacological

properties of the D1–A1 heteromeric complex (Gines

et al., 2000).

A2A receptor agonist-induced reduction of D2

receptor affinity involves conformational changes in

the binding site of D2 receptors and is caused by the

A2A–D2 heteromeric receptor complex (Salim et al.,

2000). Striatal A2A receptor seems to be involved in

the increased striatal expression of c-fos when D2

receptor signaling is interrupted (Pinna et al., 1999).

It has been suggested that the antiparkinsonian action

of A2A antagonists results from blocking the action

of A2A–D2 receptor interaction, leading to the

enhancement of D2 receptor signaling and blockade

of increased A2A receptor signaling in the denervated

striatum (Salim et al., 2000).

Recent experiments using optical sectioning

techniques found that A2A and mGluR5 are also

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TR

co-localized in rat striatal cultures (Fuxe et al., 2003).

A2A receptor-induced phosphorylation of DARPP-32

at Thr-34 via an extracellular signal-regulated kinase

(ERK) pathway and induction of c-fos expression are

prominently increased in striatopallidal neurons only

when A2A and mGluR5 are co-activated (Ferre et al.,

2002; Nishi et al., 2003). This mechanism can take

place after the overactivity of glutamatergic transmis-

sion, which can induce adenosine release (Ferre and

Fuxe, 2000; Nash and Brotchie, 2000). A recent study

also showed that the mGluR5-mediated effect in the

striatum is abolished by blockade of A2A receptors

(Domenici et al., 2004). Additionally, it has been

demonstrated that A2A and mGluR5 could synergisti-

cally reduce the affinity of D2 receptors in the striatum

(Ferre et al., 1999). Interestingly, chronic but not acute

treatment with an mGluR5 antagonist can reverse par-

kinsonian symptoms in a rat model of PD (Breysse

et al., 2002). This effect may be caused by desensitiza-

tion of the A2A–mGluR5 heteromeric complex, leading

to removal of the blockade of D2 receptor-induced sig-

naling effect (Fuxe et al., 2003). According to all these

results, it has been suggested that the striatal A2A–D2–

mGluR5 multimeric receptor complexes may be

involved in striatal plasticity and could be relevant for

the management of PD (Ferre et al., 2002; Fuxe et al.,

2003).

2.9.4. Neuroprotection by A2A receptor antagonists

Striatal A2A receptor stimulation by increasing the

release of GABA in the GPe reduces the activity of

the GABAergic projection from the GPe to the STN

and leads to disinhibition of the STN. Since STN pro-

jects to SNc, enhanced release of glutamate from STN

can exert an excitotoxic effect on the dopaminergic

nigrostriatal neurons and, conversely, A2A antagonists

may protect dopaminergic neurons from degeneration

(Blandini et al., 2000; Schwarzschild et al., 2003).

The stimulation of striatal glutamate release by

mGluR5 agonists also involves A2A receptors (Pintor

et al., 2000). According to the positive regulation of

striatal glutamate outflow by A2A receptor activation,

one of the other mechanisms responsible for the neuro-

protective effects of A2A receptor antagonists could be

the modulation of striatal glutamate release. In agree-

ment with this hypothesis, blockade of striatal A2A

receptor reduced quinolinic acid-induced excitotoxi-

city in the rat striatum (Popoli et al., 2002). In addi-

tion, deficient A2A receptor mice were shown to be

more resistant to MPTP-induced dopaminergic degen-

eration (Chen et al., 2001). Moreover, activation of

A2A receptors in cultured glial cells from the cortex

and brainstem increased extracellular glutamate levels,


while A2A antagonists reduced glutamate efflux (Li

et al., 2001; Nishizaki et al., 2002). It has been sug-

gested that A2A receptor regulation of glial GLT1

may be implicated in this effect (Schwarzschild

et al., 2003). Interestingly, more recently it has been

shown that A2A receptor antagonists prevent the

increase in striatal glutamate levels by removal of

the inhibitory influence exerted by A2A receptors on

glutamate uptake (Pintor et al., 2004).

Nevertheless, a recent study suggests that, whereas

presynaptic A2A receptor activation by facilitation of

glutamate release has excitotoxic effects, postsynaptic

A2A receptor stimulation by induction of trophic

factors and inhibition of NMDA effects is potentially

beneficial (Tebano et al., 2004). According to the

results of this study, it has been suggested that the

neuroprotective potential of A2A antagonists is mainly

evident in models of neurodegenerative diseases in

which presynaptic mechanisms play a prominent role

(Tebano et al., 2004).

In conclusion, A2A receptor antagonists, based on

their application in the improvement of parkinsonian

symptoms and their neuroprotective effects, seem to

be promising therapeutic candidates in PD.


2.10. Endocannabinoids

The principal psychoactive component of Cannabissativa (for example, marijuana and hashish) is �9-tet-

rahydrocannabinol (�9-THC) (Matsuda et al., 1990).

�9-THC exerts a large number of effects in the CNS,

including analgesia (Richardson et al., 1998), cata-

lepsy (Compton et al., 1996), impairment of learning

and memory (Mallet and Beninger, 1998) and positive

reinforcement (Martellotta et al., 1998).

Two endogenous ligands for cannabinoid receptors,

termed endocannabinoids, have been identified in the

brain (Kreitzer and Regehr, 2002). Endocannabinoids

have been shown to be involved in the retrograde reg-

ulation of synaptic transmission at a variety of brain

synapses. Furthermore, a close interaction between

dopamine and endocannabinoids in motor function

has also been suggested (Beltramo et al., 2000; Mesch-

ler and Howlett, 2001). The mechanism of action of

these retrograde signals is of interest, especially in

association with activity-dependent synaptic plasticity

related to the processing and storage of motor informa-

tion in the BG.

2.10.1. Brain synthesis of endocannabinoids

Unlike neurotransmitters and neuropeptides, which are

released from synaptic terminals via vesicle secretion,

DI

endocannabinoids are produced and released on

demand (Piomelli, 2003).

Anandamide was the first molecule isolated and

characterized as an endocannabinoid (Devane et al.,

1992). Anandamide is synthesized from the cleavage

of phospholipid precursor, N-arachidonoylphosphati-dylethanolamine (NAPE) by phospholipase D (PLD)

(Di Marzo et al., 1994):

44 P. SAMA

PhosphatidylethanolamineN-acyltransferse

NAPE

PLDAnandamide

A second endocannabinoid, 2-arachidonylglycerol,

is formed through a distinct biosynthetic pathway,

involving phospholipases and diacylglycerol lipase,

from phosphatidylinositol (Sugiura et al., 1995; Stella

et al., 1997):

PI

PLC

PLA12-AG

1,2 DAG

Lyso-PI Lvso-PLC

DAG lipase

PLC, phospholipase C

PLA1, phospholipase A1

The formation of these endocannabinoids can be

initiated by postsynaptic membrane depolarization,

which opens voltage-gated Ca2þ channels. The

increase in the concentration of intracellular Ca2þ then

activates enzymes involved in the synthesis of endo-

cannabinoids from lipid precursor (Alger, 2002; Wil-

son and Nicoll, 2002). Endocannabinoid synthesis

can also be triggered by activation of G-protein-

coupled receptors. For example, the dopamine D2

receptor agonist quinpirole causes an increase in ana-

ndamide levels in the rat striatum, which is prevented

by the dopamine D2 receptor antagonist raclopride

(Giuffrida et al., 1999). Activation of group I mGluRs

and also muscarinic acetylcholine receptors could

enhance the release of endocannabinoids (Alger,

2002; Wilson and Nicoll, 2002).

2.10.2. Release, diffusion and uptake

of endocannabinoids

Physiological experiments have shown that endo-

cannabinoids could leave postsynaptic cells to acti-

vate cannabinoid receptors on adjacent presynaptic

axon terminals (Wilson and Nicoll, 2002; Piomelli,

2003). Extracellular lipid-binding proteins such as

lipocalins, which are expressed at high levels in

the brain, may help to deliver endocannabinoids

to their cellular targets (Piomelli, 2003). Recently,

it has been shown that postsynaptic transport

mechanisms are responsible for the release of endo-

cannabinoid from striatal medium spiny neurons

(Ronesi et al., 2004).

How far are the endocannabinoid molecules able to

travel from their point of release to affect other cells?

In dorsolateral striatum, physiological activation of

cells does not cause spread of endocannabinoids to

nearby cells unless endocannabinoid uptake is inhib-

ited by the transport inhibitor AM-404 (Gerdeman

et al., 2002). Therefore, it has been suggested that

endocannabinoids are quite local signals, but condi-

tions that favor their synaptic synthesis and release

with a reduction in endocannabinoid uptake may

induce their diffusion to neighboring cells (Alger,

2002; Wilson and Nicoll, 2002). After having been

released into the extracellular space, two mechanisms

could attenuate endocannabinoid signaling in the

brain: first, transport of endocannabinoid into cells,

which is not mediated by transmembrane Naþ gradi-

ents but by specific transport protein present in both

neurons and glial cells (Beltramo et al., 1997; Pio-

melli, 2003). Indeed, an antagonist of this transporter,

AM-404, potentiates the effect of exogenous ananda-

mide on cultured neuron (Beltramo et al., 1997). Sec-

ond, after being removed from the extracellular

space, endocannabinoids are degraded by intracellular

enzymes. Anandamide is catalyzed (broken) to arachi-

donic acid and ethanolamine by fatty acid amine

hydrolase (FAAH) (Wilson and Nicoll, 2002; Piomelli,

2003).

ET AL.

2.10.3. Receptors, signal transduction and function

Two forms of cannabinoid receptor, CB1R and CB2R,

which belong to the family of G-protein-coupled

receptors, have been cloned (Matsuda et al., 1990;

Onaivi et al., 2002). Brain endocannabinoids, ananda-

mide and 2-arachidonylglycerol, exert most of their

action in the brain via CB1R. CB1R is one of the most

abundant neuromodulatory receptors in the brain and

is expressed at high levels in the BG (Matsuda et al.,

1990; Herkenham et al., 1990; Wilson and Nicoll,

2002). CB2R is enriched in immune tissues but absent

from the brain (Munro et al., 1993). New data demon-

strate that brains of CB1R-deficient mice have still

significant binding with a synthetic cannabinoid ago-

nist (Breivogel et al., 2001). These data may suggest

TR

the existence of a third cannabinoid receptor (Wilson

and Nicoll, 2002).

In the striatum CB1Rs are twice as numerous as

dopamine D1 receptors (Herkenham et al., 1991b)

and 12 times as numerous as m opioid receptors (Sim

et al., 1996). They are expressed by three distinct

neuronal elements:

1. 89.3% of GABAergic striatal projection neurons in


matrix and 56.4% of medium spiny neurons in

patch are labeled for CB1R (Fusco et al., 2004).

2. Local circuit of GABAergic interneurons also

expresses CB1Rs (Hohmann and Herkenham,

2000). Recent studies demonstrate that 86.5% of

parvalbumin interneurons, which mediate a feed-

forward inhibition on striatal projection neurons,

contain CB1Rs. One-third (30.4%) of NOS-con-

taining neurons and one-third (39.2%) of striatal

cholinergic interneurons are also labeled for

CB1Rs (Fusco et al., 2004).

3. CB1Rs are also localized in glutamatergic corti-

costriatal terminals (Gerdeman and Lovinger,

2001, Huang et al., 2001, Piomelli, 2003). CB1Rs

are also abundant in the globus pallidus and the

SNr, the output nuclei of the BG (Herkenham

et al., 1991a; Piomelli, 2003).

The activation of CB1Rs causes inhibition of both N-

type and P/Q-type Ca2þ channels which are known to reg-

ulate neurotransmitter release (Pertwee, 1997; Twitchell

et al., 1997; Huang et al., 2001), and stimulation of G-

protein-coupled inward-rectifying Kþ channels (Henry

and Chavkin, 1995). Inhibition of adenylyl cyclase and

consequent decrease in cAMP concentration, stimulation

of A-type Kþ currents (Childers and Deadwyler, 1996)

and activation of kinases that phosphorylate tyrosine,

serine and threonine residues in proteins (Piomelli,

2003) also contribute to CB1R-mediated signaling.

Depolarization-induced suppression of inhibition

and of excitation are the most convincing examples

of rapid retrograde signaling in the brain produced by

endocannabinoids (Alger, 2002). A transient depolari-

zation of a postsynaptic cell elicits Ca2þ-dependentendocannabinoid production. The endocannabinoid

could then activate CB1Rs on inhibitory terminals to

reduce GABA release from postsynaptic axons (Alger,

2002; Kreitzer and Regehr, 2002; Wilson and Nicoll,

2002). It has been found that CB1R activation could

inhibit GABAergic responses evoked by local stimula-

tion of the striatum (Szabo et al., 1998). In addition,

local administration of cannabinoid agonists in the

striatum inhibits GABA release and affects motor

behaviors (Romero et al., 2002). The expression of

CB1Rs on striatal parvalbumin and NOS GABAergic

interneurons as well as cholinergic interneurons

demonstrates the involvement of endocannabinoid

(anandamide) in the modulation of motor activity.

Interestingly, the ability of cannabinoids to inhibit

the release of acetylcholine has been demonstrated in

hippocampus and prefrontal cortex both in vivo and

in vitro (Schlicker and Kathmann, 2001). However, if

locally released anandamide has access to these striatal

interneurons or this endocannabinoid primarily acts on

medium spiny neurons and corticostriatal afferents is

not yet clearly known (Piomelli, 2003). Anandamide

via activation of CB1Rs can also mediate the inhibi-

tion of glutamatergic transmission in the striatum

(Gerdeman and Lovinger, 2001) and SNr (Szabo

et al., 2000). However, whether such effects reflect

the existence of regional depolarization-induced sup-

pression of excitation phenomenon is an important

question to be addressed (Piomelli, 2003).

The release of anandamide from medium spiny

neurons is stimulated by membrane depolarization,

increase in the intracellular Ca2þ levels and also

dopamine D2 receptor activation (Giuffrida et al.,

1999). More recently, it has been shown that ananda-

mide release is involved in the induction of a long-

lasting form of plasticity, LTD of excitatory transmis-

sion in the striatum (Gerdeman et al., 2002). Striatal

LTD is expressed as a decreased probability of gluta-

mate release at corticostriatal synapse (Choi and

Lovinger, 1997). LTD is absent in the striatum of

CB1R-deficient mice and is blocked by a CB1R-

antagonist (Gerdeman et al., 2002). Furthermore,

recent studies reveal that CB1R activation is neces-

sary for induction, but not the maintenance, of striatal

LTD since CB1R-antagonists reverse agonist-induced

synaptic depression but do not alter established LTD

(Ronesi et al., 2004). This transient action interacts

with another putative presynaptic signal to estab-

lished LTD.

As previously reported, increased activity of corti-

costriatal neurons in PD reflects the loss of dopamine

D2 receptor-mediated control of glutamatergic trans-

mission (Cepeda et al., 2001). Recent studies have

revealed that CB1R activation reduces the release of

glutamate in the striatum via an indirect pathway

involving inhibition of glutamate transport function.

This results in an increase in the extracellular gluta-

mate concentration, which activates the presynaptic

mGluRs. Finally, the latter mediates reduction of

glutamate release and depression of corticostriatal

synaptic transmission (Brown et al., 2003). Interest-

ingly, dopamine D2 and CB1Rs share the same effect

in the negative regulation of corticostriatal inputs

(Meschler and Howlett, 2001).

After dopamine denervation in 6-OHDA lesioned

rats, increased levels of anandamide are paralleled by


DI

an abnormal downregulation of anandamide mem-

brane transporter and FAAH activity, without changes

in the level of CB1R and anandamide binding to this

receptor (Gubellini et al., 2002). However, these

changes in endocannabinoid system as a compensatory

mechanism, trying to control abnormal overactivity of

glutamatergic transmission in the striatum, seem not to

be sufficient (Gubellini et al., 2002; Maccarrone et al.,

2003). Recently, it has been shown that further

increase of anandamide by inhibition of its degradation

and blockade of FAAH restores the normal corticos-

triatal function (Maccarrone et al., 2003). In addition,

depression of striatal glutamatergic activity produced

by FAAH blockade was much stronger than in sham-

operated and levodopa-treated lesioned rats. Therefore,

inhibition of FAAH may be beneficial to decrease

abnormal synaptic transmission in PD (Maccarrone

et al., 2003). Moreover, the beneficial effect of the

CB1R agonist nabilone to decrease levodopa-induced

dyskinesias in the parkinsonian MPTP monkeys and

parkinsonian patients has also been reported (Sieradzan

et al., 2001; Fox et al., 2002). Dopamine D1 receptor

activation of adenylyl cyclase can be blocked by CB1R

stimulation (Meschler and Howlett, 2001). Therefore,

this beneficial effect of CB1R activation to improve

levodopa-induced dyskinesias could be explained by

reduction of both overactive glutamatergic transmission

in the striatum and enhanced signaling by dopamine

D1 receptor (Brotchie, 2003).

CB1R activation could also affect motor activity by

modulating both inhibitory and excitatory input to SNr-

GPi from striatum and STN, respectively (Sanudo-Pena

et al., 1999). Finally, CB1R activation of the endocannabi-

noid system could provide an on-demand protective cas-

cade against excitotoxicity and may become a promising

therapeutic target for the treatment of neurodegenerative

diseases (Marsicano et al., 2003).

Together, these results suggest that endocannabi-

noid signaling provides a mechanism for regulating

synaptic strength in the BG, which are involved in

movement control and in pathologies such as PD.

46 P. SAMA

2.11. Other putative neurotransmitters in thebasal ganglia

2.11.1. Nitric oxide and carbon monoxide

Nitric oxide (NO) is formed in neurons through the

oxidation of the amino acid arginine by the enzyme

NOS, a Ca2þ-calmodulin-dependent enzyme, in

response to glutamate acting through NMDA receptors

and requiring an influx of Ca2þ ions (Kandel, 2000b).

The half-life of NO is considered to be less than a few

seconds. However, it is not a polar molecule and

therefore can easily penetrate neuronal membranes to

diffuse to adjacent neurons (Ohkuma and Katsura,

2001).

The major action of NO, as a gaseous messenger,

is to stimulate the production of cyclic guanosine

monophosphate (cGMP) by the intracellular enzyme

guanylyl cyclase. Two forms of guanylyl cyclase,

the enzyme that converts GTP to cGMP, have been

identified. One form is a membrane protein with an

extracellular receptor domain and an intracellular

catalytic domain that synthesized cGMA. cGMP is

a freely diffusible cytoplasmic second messenger

that activates protein kinases (Kandel, 2000b). It

has been reported that NO can also stimulate the

release of various types of neurotransmitter, such

as dopamine, glutamate, acetylcholine and GABA

(Ohkuma and Katsura, 2001). The mechanisms for

the NO-induced release of neurotransmitters are not

well understood; however, this can be mediated via both

Ca2þ-dependent and -independent processes (Ohkuma

and Katsura, 2001). A part of Ca2þ-dependent releaseof neurotransmitters by NO is due to the opening of vol-

tage-dependent Ca2þ channels followed by increased

Ca2þ influx subsequent to neuronal membrane depolari-

zation induced by NO (Ohkuma and Katsura, 2001).

Furthermore, NO shows cytotoxic effects and plays a

role in various neurological diseases, which are caused

by excessive production of NO (Ohkuma and Katsura,

2001). Accordingly, it has been reported that 7-nitroin-

dazole, a relatively selective inhibitor of the neuronal

NOS, can protect against MPTP-induced neurotoxicity

in experimental animals (Hantraye et al., 1996). A recent

study also suggests that the protective effect of NOS

inhibitor may be partly produced by the reduction of

neuronally derived NO and peroxynitrite caused by

MPTP (Watanabe et al., 2004). Therefore, the neuronal

NOS inhibitors may have therapeutic efficiency in

neurodegenerative diseases such as PD (Watanabe

et al., 2004).

Recent pharmacological and genetic experiments

have identified NO as one of the possible retrograde

messengers involved in synaptic plasticity (Kandel,

2000a). Striatal NOS-positive interneurons represent

the main source of NO in the striatum (Centonze

et al., 1999). It has been suggested that dopamine sti-

mulates NO production by activating D1 receptors

located on striatal NOS-positive neurons. NO, in turn,

might cooperate with postsynaptic D2 receptors to

induce striatal LTD (Calabresi et al., 1999b; Centonze

et al., 2003c). Therefore, these interneurons, by receiv-

ing direct cortical inputs and innervating the medium

spiny neurons, mediate feed-forward processing of

the cortical input to the striatal projection neurons

(Centonze et al., 1999).

ET AL.

TR

Carbon monoxide (CO) is also considered as a gas-

eous neurotransmitter (Deutch and Roth, 2003). CO is

produced endogenously by the NADPH-dependent

enzymatic peroxidation of microsomal membrane

lipids and by heme oxygenase (HO) enzymes (Riedl

et al., 1999). The brain contains the two isoforms of

HO, the oxidative stress-inducible HO-1 and the con-

stitutive HO-2. In PD prominent annular HO-1 immu-

noreactivity is found in cytoplasmic Lewy bodies

(Schipper, 2004).

2.11.2. Cytokines and growth factors

The cytokine (‘cell movement factor’) family is a

group of secreted proteins that mediate diverse biolo-

gical responses such as changes in the immune system

(interleukins), tumor cytotoxicity (tumor necrotic fac-

tors) and inhibition of viral replication or cell growth

(interferons) (Oppenheim and Johnson, 2003). Many

cytokines important for the development and mainte-

nance of peripheral organs are also widely expressed

in the nervous system, although their role in the brain

has yet to be defined. The neuropoietic cytokines, cili-

ary neurotrophic factor and leukemia inhibitory factor,

possess widespread neurotrophic activity (Oppenheim

and Johnson, 2003). Cytokines and growth factors

have been grouped into families based on their protein

sequences and receptor usage rather than on their bio-

logical properties.

The growth factor family is a group of proteins that

support the growth, development, plasticity, differen-

tiation and maintenance of neurons. Growth factors

are stored and released from neurons, suggesting that

they may also act as neurotransmitters (Oppenheim

and Johnson, 2003).

Representative members of the neurotrophic factor

family (also called neurotrophin or nerve-feeding

factors) include nerve growth factor, brain-derived

nerve growth factor (BDNF), neurotrophins or

nerve-feeding factors (NT-3, NT4/5 and NT-6). The

neurotrophins act through high- and low-affinity

receptors. There are three tyrosine receptor kinase

or trk receptors – trkA, trkB and trkC – accounting

for most of the biological responses of neurons to

neurotrophins. Each member of the neurotrophin

family binds with one or more of the trk receptors.

All neurotrophins bind p75LNTR or the low-affinity

neurotrophin receptor; this receptor lacks a cytoplas-

mic kinase domain. p75LNTR can facilitate ligand

binding to, and enhance signaling through, trkA and

independently initiate signaling. Splice variants of

trks lacking signaling capabilities are also present

and they may modulate neurotrophin activity by lim-

iting access of full-length receptors to their ligand


(Huang and Reichardt, 2001; Oppenheim and John-

son, 2003).

Neurotrophins and their receptors are present in the

BG and have a specific striatal distribution. The recep-

tor for BDNF, trkB, is the most abundant and is mainly

found in medium-sized spiny projecting neurons,

whereas these neurons contain lower levels of the trkC

receptor for NT-3 (Merlio et al., 1992). In contrast, the

high-affinity receptor for nerve growth factor, trkA, is

restricted to cholinergic interneurons (Holtzman et al.,

1995). In agreement with their receptor distribution,

BDNF and NT-3 have trophic effects on GABAergic

projecting neurons (Mizuno et al., 1994; Ventimiglia

et al., 1995; Ivkovic et al., 1997) and nerve growth

factor on striatal cholinergic neurons (Martinez et al.,

1985; Mobley et al., 1985). Striatal neurotrophins

and their receptors were shown to be regulated by

ionotropic and metabotropic glutamate receptor ago-

nists (Alberch et al., 2002). In the substantia nigra a

partial 6-OHDA lesion of dopaminergic neurons

increases BDNF mRNA levels in the subtantia nigra

pars reticulata (Aliaga et al., 2000).

Representative members of the tissue growth factor

family includes glial-derived neurotrophic factors

(GDNF), insulin-like growth factors (IGF), tumor

growth factors, epidermal growth factors and platelet-

derived growth factors (Oppenheim and Johnson,

2003). Because knowledge of the basic cellular biology

of each growth factor is still incomplete, those more

concerned with the BG will be discussed briefly. GDNF

signals through the receptor tyrosine kinase Ret (Jing

et al., 1996). GDNF family ligands are potent survival

factors of midbrain dopamine neurons (Saarma, 2000).

Intracerebral injections of GDNF can provide almost

complete protection of nigral dopamine neurons against

6-OHDA or MPTP-induced damage, promote axonal

sprouting and regrowth of lesioned dopamine neurons

and stimulate dopamine turnover and function in neu-

rons spared from the lesion (Bjorklund et al., 1997;

Gash et al., 1998). Five PD patients receiving GDNF

showed significant clinical improvement and reduction

of dyskinesias without side-effects (Gill et al., 2003).

Furthermore, GDNF was shown by positron emission

tomography to increase dopamine storage significantly

in the putamen, suggesting a direct GDNF effect on

dopamine function (Behrstock and Svendsen, 2004).

The main source of IGF-I is the liver but the brain

also synthesizes this peptide. Furthermore, systemic

IGF-I enters the brain, thus both locally synthesized

and peripheral IGF-I may affect brain function (Car-

dona-Gomez et al., 2001). IGF-I acts through the

IGF-IR, a member of the growth factor tyrosine kinase

receptor family that signals through PI3 kinase and

MAPK cascade (LeRoith et al., 1993). IGF-I was


CorticostriatalNerve terminal

Glutamate

Dopamine

Endogenous

opioids

Endogenousopioids

Opioid receptor

Opioidreceptor

Adenosine

NMDAreceptor

cAMP signaling cascade

Ca2+

ATP

ATPcAMP

cAMP

-

D2

GsAc A2a

+

-

+

-

-

Protein kinase activation

CREB-PFos-P

Motor behavior

IEG

Short termresponses

LOG

Long-term adaptiveresponses

DARPP-32 phosphorylation

PP-1 inhibition

-

CorticostriatalNerve terminal

Protein kinase activation

Synapticvesicle

Synapticvesicle

CREB-PFos-P

Motor behavior

Glutamate

Acetylcholine

M2 or M3mACh receptor

Opioid receptor

Adenosine

NMDAreceptor

IEG

Short termresponses

LOG

Long-term adaptiveresponses

DARPP-32 phosphorylation

PP-1 inhibition

cAMP signalingcascade

Ca2+

ATP

ATP

cAMP

cAMP

-

D1

Gs

A1

+

+-

- Opioidreceptor

Gi Ac

GABAergic striato-pallidal neuron

GABAergic striato-nigral neuron

-Acetylcholine

M2 or M3mACh receptor

M1 mAChreceptor

-

Ca2+

PP-2B-

+

PP-2B-

+

M1 mAChreceptor

Ca2+ +

m Opioidreceptor

Gi

Ac

Ac

-

48

P.SAMADIETAL.

TR

shown to protect striatal neurons against quinolinic

acid toxicity (Alexi et al., 1999) and dopaminergic

nigral neurons against 6-OHDA (Guan et al., 2000).

Interestingly, IGF-I was shown to interact with estro-

gens in the brain and this has been implicated in neu-

roprotection (Cardona-Gomez et al., 2001).


2.12. Functional integrationof neurotransmitters

Acquisition of motor or procedural learning is implicit

and memory is reflected by a progressive reduction of

the response time or the error rate over repeated expo-

sure to the procedure (Dujardin and Laurent, 2003).

The striatum, the largest input structure of the BG

circuit that receives afferents from all regions of the

cerebral cortex, is a part of the motor learning system

of the mammalian brain (Graybiel, 2004). A functional

deficit in this system induced by the loss of nigrostria-

tal neurons in PD contributes to the neurological disor-

ders seen in parkinsonian patients. In humans, the

dorsal striatum is essential not just for motor learning

but also for acquiring the gradual, incremental learning

of stimulus–response association that is the character-

istic of implicit or habit learning (Knowlton et al.,

1996). In humans and in other animals, habit learning

can be dissociated from explicit learning and from

affect-related learning mediated by the hippocampal–

medial temporal cortical systems and limbic struc-

tures, respectively (Graybiel, 1998). Lesions of the

dorsal striatum in rats and in monkeys lead to the

selective impairment of the stimulus–response (habit)

learning without affecting spatial task, a form of expli-

cit memory (Packard and McGaugh, 1992; Fernandez-

Ruiz et al., 2001). In addition, in patients with PD,

impaired performance of stimulus–response learning

but entirely normal declarative memory has also been

demonstrated (Knowlton et al., 1996).

In cellular transduction pathways, long-term storage

of implicit memory involves the cAMP, PKA, MAPK

and CREB pathways (Kandel et al., 2000; Kandel,

Fig. 2.6. For full color version, see plate section. Interaction of d

the striatum and possible sequence of events leading to motor b

between its kinases and phosphatases. In the striatum DARPP-32

pathways (Greengard, 2001). Increase in the level of cyclic adeno

kinases and phosphorylation of dopamine- and cAMP-regulated

phosphorylation converts DARPP-32 from an inactive molecule

trols the state of phosphorylation and activity of numerous physi

such as cAMP-response element-binding protein (CREB) and fos

onset genes (LOG), following activation of transcription factors, m

responsible for adaptive synaptic plasticity leading to motor lear

2001). cAMP mediates many intracellular events that

are involved in long-term cellular adaptation, includ-

ing phosphorylation of DARPP-32 at Thr-34 in striatal

output neurons and consequently regulation of activity

of transcription factors such as CREB and fos-family

(Greengard, 2001).

Dopamine and glutamate, as well as their interac-

tions, are key elements in the control of the neuronal

plasticity in the corticobasal ganglia circuit affecting

motor learning (Canales et al., 2002). Some of the

changes occurring during learning involve altering

the parameters of corticostriatal transmission (Gray-

biel, 1998). When corticostriatal excitation and dopa-

minergic activation are temporally coordinated, they

trigger intracellular signaling that leads to short- and

long-term changes in gene expression and also long-

lasting enhancement of synaptic strength in medium

spiny neurons (Fig. 2.6) (Wickens et al., 1996; Kelley

et al., 2003). Accordingly, recent studies have pro-

posed that learning and memory of habitual move-

ments involve the relative balance between dopamine

and glutamate receptor signaling that determines

which intracellular cascades will be activated in which

striatal output neurons (Gerfen et al., 2002).

More recently it has been demonstrated that dopa-

mine, by filtering less active inputs, via activation of

presynaptic D2 receptors, reinforces particular subsets

of corticostriatal afferents (Bamford et al., 2004). On

the other hand, activation of NMDARs recruits dopa-

mine D1 receptors to the plasma membrane and thus

increases D1-like receptor signaling pathway (Scott

et al., 2002; Pei et al., 2004). This D1–NMDA interac-

tion plays an essential role in the control of learning-

related plasticity (Kelley et al., 2003). In addition to

dopamine and glutamate receptors, striatal cholinergic

receptors also have a significant role in triggering the

intracellular changes responsible for corticostriatal

synaptic plasticity (Calabresi et al., 2000b; Ragozzino,

2003). Indeed, the release of acetylcholine in different

neuronal systems provides a marker of activation of

those systems during learning (Chang and Gold, 2003).

Furthermore, GABAergic interneurons, including


opamine, adenosine, glutamate, acetylcholine and opioids in

ehavior. The phosphorylation state of a protein is a balance

plays a key role in the interactions amongst various signaling

sine monophosphate (cAMP) causes the activation of protein

phosphoprotein (DARPP-32) at threonine 34 (Thr-34). The

into an inhibitor of protein phosphatase-1 (PP-1), which con-

ologically important effectors, including transcription factors

-family. Modification of immediate early genes (IEG) or late-

ay trigger the short- and long-term adaptive changes that are

ning. Modified from Samadi et al. (2003).

DI ET AL.

NOS-containing neurons, by modulating the activity of

medium spiny neurons in response to cortical inputs,

also play an important role in the expression of synap-

tic plasticity at corticostriatal synapses (Centonze

et al., 1999, 2003c).

Therefore, the striatum, by processing the informa-

tion flow from various inputs and sending output to

targets that generate behaviors (Grace, 2000), plays a

key role in adaptive plasticity in corticobasal ganglia

as well as in pathological responses in PD.

50 P. SAMA

Acknowledgments

The authors would like to thank Laurent Gregoire for

helping in the management of the references in the text

and Gilles Chabot for preparing the figures. This work

is supported by grants from the Canadian Institutes of

Health Research (CIHR) to TDP, PJB and CR. PS

holds a fellowship from CIHR-RX&D.

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Functional neurochemistry of the basal ganglia