Monoamine neurotransmitters

Dr. M.G.SRINIVAS

ROLE OF MONOAMINE

NEUROTRANSMITTERS

IN PSYCHIATRY

CONTENTS DISCOVERY OF 1ST NEUROTRANSMITTER

DEFINITION OF NEUROTRANSMITTER

CRITERIA FOR NEUROTRANSMITTER

7 PROCESSESS IN NEUROTRANSMITTER ACTION

FATE OF NEUROTRANSMITTERS

CLASSIFICATION OF NEUROTRANSMITTERS

BIOGENIC AMINES

DOPAMINE

SEROTONIN

EPINEPHRINE & NOREPINEHRINE

HISTAMINE

ACETYLCHOLINE

DISCOVERY OF 1st

NEUROTRANSMITTER

Acetylcholine - The first neurotransmitter

identified, in 1926, by Otto Loewi.

He demonstrated that Acetylcholine carried a

chemical signal from vagus nerve to the heart

that slowed the cardiac rhythm.

Got NOBEL in physiology & medicine

in the year 1936

NEUROTRANSMITTERS

DEFINITION

Neurotransmitters are chemical signals

released from presynaptic nerve terminals into

the synaptic cleft.

The subsequent binding of neurotransmitters

to specific receptors on postsynaptic neurons

(or other classes of target cells) transiently

changes the electrical properties of the target

cells, leading to an enormous variety of

postsynaptic effects.

CRITERIA FOR NEUROTRANSMITTERS

1. Molecule is synthesized in neuron

2. Molecule is present in presynaptic neuron & is

released on depolarisation in physiologically

significant amount

3. When administered exogenously as a drug,

the exogenous molecule mimics the effect of

endogenous neurotransmitter

4. A mechanism in neurons or synaptic cleft acts

to remove or deactivate the neurotransmitter

MAJOR STEPS IN

NEUROTRANSMITTER PROCESSING

are:

1. SYNTHESIS

2. STORAGE

3. RELEASE

4. RECEPTION

5. INACTIVATION

FATE OF NEUROTRANSMITTERS

1. It is consumed ( broken down or used up) at

postsynaptic membrane leading to action

potential generation.

2. Degraded by enzymes present in synaptic

cleft.

3. Reuptake mechanism( reutilization), this is the

most common fate.

CLASSIFICATION OF

NEUROTRANSMITTERS

Amine neurotransmitters:

1. Catecholamines

Dopamine

norepinephrine

epinephrine

2. Indolamines

Serotonin (5-hydroxytryptamine; 5-HT)

3. Histamine

4. Acetylcholine

All monoaminergic systems share common

anatomical features.

Each has a cluster of cell bodies in a few

restricted sub cortical or brainstem regions,

which then send long and extensively branched

axonal processes into

multiple cortical and limbic target regions.

The precise evolutionary reasons for this

organization are unclear, although it could in

principle allow monoaminergic systems to

coordinately control spatially distant brain

regions.

DOPAMINE

DOPAMINE HISTORY

The function of DA as

neurotrasmitter was discovered

in1958 by arvid carlsson &

nils ake hillarp.

ARVID CARLSSON got NOBEL

for physiology or medicine in

2000 for showing that DA is not

Just a precursor of NE & E but a

Neurotransmitter as well.

DOPAMINE

DEGRADATION

DOPAMINE PATHWAYS

5 dopamine pathways in the brain:

1. The MESOLIMBIC DA pathway,

2. The MESOCORTICAL DA pathway,

3. The NIGROSTRIATAL DA pathway,

4. The TUBEROINFUNDIBULAR DA

pathway,

5. The THALAMIC DA pathway

DA pathways in the brain can explain the

symptoms of schizophrenia as well as the

therapeutic effects

and side effects of antipsychotic drugs.

(1) THE MESOLIMBIC DOPAMINE PATHWAY

projects from the midbrain ventral

tegmental area to the nucleus accumbens, a

part of the limbic system

MESOLIMBIC PATHWAY role in

-emotional

behaviour

-pleasure

-motivation

-reward

HYPERACTIVITY OF MESOLIMBIC

PATHWAY

-positive psychotic symptoms

accompanying mania, depression,

dementia.

INCLUDES:

-delusion

-hallucination

-aggression

-hostility

-euphoria in drug abusers

HYPO ACTIVITY OF MESOLIMBIC

PATHWAY

lack of general motivation & interest,

anhedonia

negative symptoms,

drug abuse.

(2) MESOCORTICAL DOPAMINE PATHWAY

projects from midbrain ventral tegmental area

& sends its axons to areas of the prefrontal

cortex

Dorsolateral

prefrontal cortex,

DLPFC

Ventromedial

prefrontal cortex,

VMPFC

MESOCORTICAL pathway

dorsolateral prefrontal cortex role

-Regulates

cognition &

-Executive

functions

Hypofunction:

-Cognitive deterioration

-Negative symptoms in

schzophrenia

Ventromedial prefrontal cortex

Regulates-

emotions & affect

Hypo function-

affective & negative symptoms

(3) The NIGROSTRIATAL dopamine pathway,

Chronic D2 blockade –leads to neuroleptic

induced Tardive dyskinesia

(4) TUBEROINFUNDIBULAR DA PATHWAY

TUBEROINFUNDIBULAR DA PATHWAY

Activity - decrease in prolactin release

• Postpartum- increase in prolactin

• Antipsychotics - increase in prolactin

-galactorrhoea

-amenorrhoea

-sexual

dysfunction

(5) THALAMIC DA PATHWAY

arises from multiple sites,

-periaqueductal gray,

-ventral

mesencephalon,

-hypothalamic

nuclei, &

-lateral parabrachial

nucleus,

projects to the thalamus.

Function is not currently well known.

In primates it involves in sleep & arousal

mechanisms

No evidence of it’s involvement in

SCHIZOPHRENIA

DOPAMINE RECEPTORS.

5 Types – D1, D2, D3, D4, D5.

2 Groups

D1 Like

D2 LikeD1, D5 D2,

D3,D4

Cyclic AMP Cyclic

AMP

D2-

Striatum

D3- N.

-D2 receptor was initially distinguished from

the D1 receptor on the basis of its high affinity for

butyrophenones

Moreover D2 receptor stimulation was observed

to inhibit rather than stimulate adenylate cyclase

activity.

Unlike D1-like receptors, D2 receptor may have

either a postsynaptic function or an auto receptor

function

D2 auto receptors may be found on

dopaminergic terminals or on the cell bodies and

dendrites of dopaminergic neurons, where they

mediate the inhibition of evoked dopamine

release and the inhibition of dopaminergic

neuronal firing.

Furthermore, the over expression of striatal D2

receptors during brain development can cause

long-lasting defects in prefrontal dopaminergic

transmission and working memory in mice, a

finding relevant to neurodevelopmental

hypotheses of schizophrenia.

D2 receptors are also expressed in the anterior

pituitary and mediate the

-dopaminergic inhibition of prolactin

and

-a-melanocyte-stimulating hormone

release.

Molecular cloning has revealed long and short

forms of the D2 receptor

Auto receptor functions are mediated by the

short form of this receptor

• Catalepsy induced by neuroleptics such as

haloperidol appears to be largely mediated by the

long form of the D2 receptor

• Post mortem analyses of schizophrenic

brains reveals elevations in D2 receptor

density.

• Furthermore, radioligand binding studies have

revealed

-a correlation between the clinical

efficacy of antipsychotic drugs and their

antagonist affinities for this receptor subtype.

This finding has contributed significantly to

the “dopamine hypothesis” of

schizophrenia.

The extrapyramidal side effects of

antipsychotic drugs have been attributed to

blockade of striatal D2 receptors.

D3, D4 receptors

•D3 receptor expression is highest in the nucleus

accumbens.

The highest levels of D4 receptors are expressed

in -frontal cortex,

-midbrain,

-amygdala,

-hippocampus, and medulla

D4 receptors are abundant in the heart and

kidney.

The D3 receptor may play a role in the control

of locomotion.

Elevated D4 receptor levels have been found in

post-mortem schizophrenic brains.

Moreover, the atypical antipsychotic drug

clozapine has a high affinity for the D4 receptor.

SEROTONIN

IMPORTANT PERSONALITIES IN

DISCOVERY OF SEROTONIN

A.BETTY

TWAROG

B.ARDA

GREEN

C.MAURICE

RAPPORT

D. IRVINE

PAGE

Dr. VITTORIO ERSPAMER

(1909 – 1999)

SEROTONIN

2% in CNS

98% in PERIPHERY

5HT Cannot cross B.B.B.

80% in G.I. Tract(motility

& contractility)

15-18% in Mast cells &

platelets(aggreg. & clotting)

-

Serotonin Synthesis & degradation

SEROTONIN PATHWAYS

Clustered in midline raphe nuclei of

brainstem

1)ROSTRAL NUCLEI- sends

ascending axonal projections throughout the

brain

2)CAUDAL NUCLEI – sends

projections to medulla, cerebellum & spinal cord

• Innervation of dorsal horns – implicated in

suppression of noceceptive pathways, relate to

pain relieving effect of some antidepressants

Rostral System: The Rostral midbrain cluster of cells (raphe

nuclei) are distributed throughout the midbrain, it

provides over 80% of the 5-HT innervation of the

forebrain.

Sends projections to –Prefrontal cortex,

-basal forebrain,

- striatum,

-nucleus accumbens,

-thalamus,

-hypothalamus,

-amygdala,

-hippocampus

A cluster of cells located medially and another

located dorsally

MEDIAN RAPHE NUCLEUS: sends projections

predominantly to Limbic system including

hippocampus.

DORSAL RAPHE NUCLEUS: sends

predominantly to striatum & thalamus.

Projections from these nuclei course through

the MEDIAN FOREBRAIN BUNDLE before

diverging to many regions.

Innervation of forebrain structures by

serotonergic processes is complementary to that

of NE.

OTHER SYSTEMS:

In addition to the above two pathways,

another 5-HT pathway projects partially from

one of the Rostral nuclei and partially from

two caudal nuclei to innervate the cerebellar

cortex and deep cerebellar nuclei.

There is also a widespread 5-HT projection

to structures within the brainstem, including

the locus coeruleus, several cranial

nuclei, inferior olivary nucleus, and

nucleus solitarius.

SEROTONIN RECEPTORS 7 types of serotonin receptors are now

recognized:

5-HT1 through 5-HT7, with numeroussubtypes, totaling 14 distinct receptors

The 5-HT1- is the largest serotonin receptorsubfamily,

5-HT1A,

5-HT1B,

5-HT1D,

5-HT1E, &

5-HT1F

The most intensively studied of these has beenthe 5-HT1A receptor.

5HT1A

Postsynaptic membranes of forebrain neurons

primarily in the

-hippocampus,

-cortex,

-septum and

-on serotonergic neurons,

• Where it functions as an inhibitory

somatodendritic auto receptor

•There is significant interest in the 5-HT1A

receptor as a modulator of both anxiety and

depression

The down regulation of 5-HT1A auto receptors

by the chronic administration of serotonin

reuptake blockers has been implicated in their

antidepressant effects

SSRIs may produce some behavioral effects via

increase in hippocampal neurogenesis mediated by postsynaptic 5-HT1A receptor

activation.

Partial 5-HT1A receptor agonists such as

buspirone display both anxiolytic and

antidepressant properties.

5HT1B & 5HT1D

Resemble each other in structure and brain

localization, although the 5-HT1D receptor is

expressed at lower levels.

5HT1B -implicated in the modulation of loco

motor activity levels, consistent with its high

level of expression in basal ganglia -also been

suggested as a modulator of aggression,

although 5-HT1B receptor agonist drugs have

shown limited clinical efficacy as anti aggressive

agents.

In addition, 5-HT1B and the 5-HT1D receptors

are found in the cerebral vasculature and the

trigeminal ganglion, respectively, and are

stimulated by

the anti migraine drug sumatriptan.

These receptors may therefore be involved in

the therapeutic efficacy of this drug, possibly

mediating vasoconstriction and inhibition of

noceceptive transmission.

5-HT1E Receptors

-striatum and

-entorhinal cortex,

5-HT1F Receptors

-dorsal raphe nucleus,

-hippocampus,

-cortex, and

-striatum.

5HT2A Receptors-neocortex

-platelets and

- smooth muscle

•Much recent attention has focused on the

contributions of 5-HT2A/C receptors to the

actions of atypical antipsychotic drugs such as

clozapine, risperidone and olanzapine.

•5-HT2A receptor has also been implicated in the

cognitive process of working memory, a function

believed to be impaired in schizophrenia.

5-HT2B,

-contributes to the contractile effects

of serotonin in the stomach fundus and plays

important roles in cardiac development.

5HT2C Receptors

-hippocampal formation,

-prefrontal cortex,

-amygdala,

-striatum,

-hypothalamus, &

-choroid plexus

Stimulation of 5-HT2C receptors has been

proposed to produce anxiogenic effects as well

as anorectic effects, which may result from

interactions with the

hypothalamic melanocortin and leptin pathways.

5-HT2C

-also play a role in the weight gain and

development of type II diabetes mellitus

associated with atypical antipsychotic treatment.

Alterations in 5-HT2C receptor mRNA editing

have been found in the brains of suicide victims

with a history of major depression, and SSRIs

have been shown to alter these editing patterns.

5HT3

-hippocampus,

-neocortex,

-amygdala,

-hypothalamus,

-brainstem, including the area postrema.

Peripherally-pituitary gland and enteric nervous

system

5-HT3 receptor antagonists such as

ondansetron are used as antiemetic agents and

are under evaluation as potential antianxiety and

cognitive-enhancing agents.

5HT4 –Partial agonists used in IBS

(TEGASEROD)

5HT5, 5-HT6, 5HT7 receptors – Unclear action

-Antagonists may have

antidepressant action

Serotonin is a key regulatory ofappetite,

sleep,

and

aggression.

ROLE IN PSYCHIATRY

Affective Disorders: Low levels of 5-HT and metabolites are

associated severe depression

Recent studies indicate that this type of 5-HT

influence may start early in life; low levels of

5HIAA have been found in children and

adolescents with disruptive behavioral disorders.

Obsessive Compulsive Disorder: 5-HT

dysfunction has been associated with obsessive

compulsive disorder. Accordingly, selective 5-HT

uptake blockers are used as a therapy for this

condition.

Schizophrenia: Antipsychotic drugs are

producing favourable results in treating the

symptoms of schizophrenia.

These drugs are interesting pharmacologically in

that they block both DA and 5-HT receptors as well

as ACh and HA.

Migraine Headaches. 5-HT1 agonists are

used for the treatment of migraine headache.

Insomnia. The role of 5-HT in sleep regulation

has lead to the hypothesis that reduced levels of

5-HT may induce insomnia.

Norepinephrine and Epinephrine

Norepinephrine is the more important and more

abundant of the two related neurotransmitters in

the brain, although adrenally derived epinephrine

is more abundant than norepinephrine in the

serum.

Norepinephrine and

Epinephrine

Dopamine↓Dopamine Beta-

Hydroxylase (DBH) Norepinephrine

↓ (PNMT) Epinephrine

-locus coeruleus is the origin of mostnorepinephrine in the brain followed by the

lateral tegmental area .

-Levels of epinephrine in the CNS are onlyabout 10% of the levels of norepinephrine

-Norepinephrine, as with otherCatecholamines, itself cannot cross the blood-brain barrier

SYNTHESIS

In neurons that release norepinephrine, theenzyme dopamine β-hydroxylase convertsdopamine to norepinephrine; neurons thatrelease dopamine lack this enzyme.

In neurons that release epinephrine, theenzyme phenyl ethanolamine-N-methyltransferase (PNMT) convertsnorepinephrine into epinephrine.

Neurons that release either dopamine ornorepinephrine do not have PNMT.

As with dopamine, the two major routes ofdeactivation are uptake back into thepresynaptic neuron and metabolism by MAOand COMT

PATHWAY

The major concentration of noradrenergic (and

adrenergic) cell bodies that project upward in

the brain is in the compact locus coeruleus in

the Pons.

The axons of these neurons project through

the medial forebrain bundle to the cerebral

cortex, the limbic system, the thalamus, and the

hypothalamus

NA & ADR RECEPTORS

The two broad groups: α-adrenergic receptors and the β-adrenergic receptors.

The advances of molecular biology have now sub typed these receptors into

three types of α1-receptors (α 1A, α 1B, and α1D), three types of α 2-receptors (α 2A, α 2B, α 2C), and three types of β -receptors (β 1, β 2, and β 3).

All α 1-receptors are linked to the phosphoinositol turnover system.

α -receptors inhibit formation of cAMP, andβ -receptors stimulate formation of cAMP.

NE & DRUGS The psychiatric drugs that are most associatedwith

norepinephrine are the classic antidepressantdrugs,

the tricyclic drugs.

Venlafaxine(SNRI), bupropion, andnefazodone: block the reuptake ofnorepinephrine and serotonin into thepresynaptic neuron

MAO inhibitors: block the catabolism ofnorepinephrine and serotonin.

• Thus, the immediate effect is to increase theconcentrations of norepinephrine and serotoninin the synaptic cleft.

Antidepressants: Serotonin-norepinephrine reuptake inhibitor

(SNRIs): class of antidepressant for treatment of

depression, mood disorders, anxiety.

Benzodiazepines, the primary antianxiety

drugs, decreases firing in the locus coeruleus

causing sleep

The beta-adrenergic blocking drugs

(propranolol) act as antianxiety and inhibit the

formation of traumatic memories.

HISTAMINE

HISTAMINE SYNTHESIS

HISTIDINE

L histidine

decorboxylase

HISTAMINE

This enzyme is not normally saturated with

substrate,

so synthesis is sensitive to histidine levels.

Thus peripheral administration of histidine

elevates

brain histamine levels.

HISTAMINE: ANATOMY

-Histaminergic cell bodies

-the posterior

hypothalamus termed the tuberomammillary

nucleus

project diffusely throughout brain and spinal

cord

Ventral ascending projections

course through the medial forebrain bundle and

then innervate the hypothalamus, diagonal band,

septum, and olfactory bulb.

Dorsal ascending projections

innervate the thalamus, hippocampus, amygdala,

and Rostral forebrain.

Descending projections

• travel through the midbrain central gray to the

dorsal hindbrain and spinal cord.

The hypothalamus receives the densest

histaminergic innervation, consistent with a role

for this transmitter in the regulation of autonomic

and neuroendocrine processes.

Additionally, strong histaminergic innervation is

seen in monoaminergic & cholinergic nuclei.

Histamine is distributed throughout most

tissues of the body, predominantly in mast cells.

HIATAMINE RECEPTORS

Histaminergic systems have been proposed to

modulate

-arousal,

-wakefulness,

-feeding behaviour, and

-neuroendocrine responsiveness

Four histaminergic receptor subtypes have

been identified and termed H1, H2, H3, and H4.

H1 receptors are expressed throughout the

body, particularly in smooth muscle of the

gastrointestinal tract and bronchial walls as well

as on vascular endothelial

cells.

H1 receptors are widely distributed within the

CNS, with particularly high levels in the

thalamus, cortex, and cerebellum. These

receptors are the targets of classical

antihistaminergic agents used in the treatment

of allergic rhinitis and conjunctivitis.

The well-known sedative effects of these

compounds have been attributed to their actions

in the CNS and have implicated histamine in the

regulation of arousal

and the sleep–wake cycle.

H2 receptors widely distributed throughout the body and are

found in gastric mucosa, smooth muscle, cardiac

muscle, and cells of the immune system.

Within the CNS, H2 receptors are abundantly

expressed in the neocortex, hippocampus,

amygdala, and striatum.

• H2 receptor antagonists are widely used in the

treatment of peptic ulcer disease.

•In contrast, the functional significance of central

H2 receptors is unclear, although several studies

indicate that the stimulation of these receptors

produces

antinociceptive effects.

•H2 receptors may also be involved in the control

of fluid balance, possibly along with H1 receptors,

via the stimulation of vasopressin release.

H3 receptors

located presynaptically on axon terminals

Those located on histaminergic terminals act as

auto receptors to inhibit histamine release.

In addition, H3 receptors are located on

nonhistaminergic nerve terminals, where they act

as heteroreceptors to inhibit the release of a

variety of

neurotransmitters—including norepinephrine,

dopamine, acetylcholine, and serotonin.

Particularly high levels of H3 receptor binding

are found in the frontal cortex, striatum,

amygdaloid complex, and substantia nigra

Lower levels are found in peripheral tissues

such as the gastrointestinal tract, pancreas, and

lung.

Antagonists of H3 receptors have been

proposed to have appetite suppressant, arousing,

and cognitive-enhancing properties.

The H4 receptor

Detected predominantly in the periphery, in

regions such as the spleen, bone marrow, and

leukocytes

Acetylcholine

Acetylcholine synthesis

Acetylcholine in the PNS

• Produced by:

– Motor neurons

– Parasympathetic

Both pre- and post-ganglionic neurons

– Sympathetic

pre-ganglionic neurons

some post-ganglionic neurons that

innervate sweat glands and blood

vessels

Central Cholinergic

Projections

• Basal forebrain

– Nucleus basalis (of Meynert), septal nuclei. .

• Brainstem reticular formation

(“Ponto-mesencephalotegmentalcomplex”)

– Project to thalamus, brainstem,

basal forebrain

• Cholinergic interneurons

– caudate-putamen, n. accumbens

In Alzheimer's disease there is significant

degeneration of neurons in the nucleus

basalis, leading to substantial reduction in

cortical cholinergic innervation

Cholinergic neurons may continue to fire

during REM sleep and have been proposedto play a role in REM sleep induction

The modulation of striatal cholinergic

transmission has been implicated in

the anti parkinsonian actions of

anticholinergic agents.

Peripheral acetylcholine mediates thecharacteristic postsynaptic effects of theparasympathetic system, includingbradycardia and reduced blood pressure,and enhanced digestive function.

Cholinesterase inhibitors are also used inthe treatment of myasthenia gravis, adisease characterized by weakness due toblockade of neuromuscular transmissionby auto antibodies to acetylcholinereceptors

CHOLINERGIC RECEPTORS

Two major classes of cholinergic receptors

exist:

-G-protein-coupled muscarinic receptors

and

- Nicotinic ligand-gated ion channels

In the periphery, muscarinic receptors

mediate the effects of postganglionic

parasympathetic nerve release of

acetylcholine.

Central muscarinic receptors have been

implicated in learning and memory,

sleep regulation, pain perception,

motor control, and the regulation of

seizure susceptibility.

Five muscarinic receptor subtypes have

been cloned, and these may be divided

into two families on the basis of

Types of Receptors

The M1, M3, and M5 receptors activate Gq,

leading to phosphatidylinositol turnover

and an increase in intracellular calcium

The M2 and M4 receptors may act as

inhibitory autoreceptors and

heteroreceptors to limit presynapticrelease of neurotransmitters.

M1

M1 receptors are the most abundantly

expressed muscarinic receptors in the

forebrain, including the cortex,

hippocampus, and striatum.

Pharmacological evidence has suggested

their involvement in memory and synapticplasticity

M2

In addition to being the predominant

muscarinic receptor subtype in the heart

where they function to lower heart rate, M2

receptors are widely distributed

throughout the brain

M2 receptors appear to mediate tremor,

hypothermia, and analgesia induced bymuscarinic agonists

M3

M3 receptors are found in smooth muscles

and salivary glands and appear to play a

major role in smooth muscle contraction in

the gastrointestinal and genitourinary

tracts and to mediate salivation.

Although M3 receptors are found at

modest densities in many areas of theCNS, no central role has been elucidated

M4

M4 receptors are expressed in the

hippocampus, cortex, striatum, thalamus,

and cerebellum

Striatal M4 receptors may oppose the

effects of D1 dopamine receptors and have

been implicated as putative targets for

anticholinergics used as antiparkinsonian

agents—although other muscarinicreceptor subtypes may also be involved

M5

M5 receptors are expressed in various

peripheral and cerebral blood vessels and

comprise a very small percentage of

muscarinic receptors in the brain

They may mediate cholinergic cerebralarterial vasodilation.

Nicotinic Receptors

Nicotinic acetylcholine receptors, like 5-

HT3 receptors, are members of the ligand-

gated ion channel superfamily and mediate

rapid, excitatory signaling

Nicotinic acetylcholine receptor subunits

are heterogeneous and associate in variedcombinations

These various nicotinic acetylcholine

receptor subunits can be categorized into

three general functional classes:

(1) skeletal muscle subunits (α1, β1, δ and ε),

(2) Standard neuronal subunits (α2–α6 and

β2–β4), and

(3) Subunits capable of forming homomericreceptors (α7–α9).

In the periphery, nicotinic acetylcholine

receptors are found in skeletal muscle,

autonomic ganglia, and the adrenal

medulla

In the brain, they are found in many

locations including the neocortex,

hippocampus, thalamus, striatum,

hypothalamus, cerebellum,

substantia nigra, ventral tegmentalarea, and dorsal raphe nucleus

Most nicotinic acetylcholine receptors in

mammalian brain contain either α4β2 or α7

subunit combinations

They frequently appear to mediate

presynaptic enhancement of

neurotransmitter release, influencing the

release of acetylcholine, dopamine,

norepinephrine, serotonin, as well asGABA and glutamate

Nicotinic receptors have been implicated

in cognitive function, especially working

memory, attention, and processing speed

Cortical and hippocampal nicotinic

acetylcholine receptors appear to be

significantly decreased in Alzheimer's

disease, and nicotine administration

improves attention deficits in some

patients

The acetyl cholinesterase inhibitor

galantamine used in the treatment of

Alzheimer's disease also acts to positivelymodulate nicotinic receptor function.

The α7 nicotinic acetylcholine receptorsubtype has been implicated as one ofmany possible susceptibility genes forschizophrenia, with lower levels of thisreceptor being associated with impairedsensory gating

Some rare forms of the familial epilepsysyndrome autosomal dominant nocturnalfrontal lobe epilepsy (ADNFLE) areassociated with mutations in the α4 or β2

subunits of the nicotinic acetylcholinereceptor

Finally, the reinforcing properties of

tobacco use are proposed to involve the

stimulation of nicotinic acetylcholine

receptors located in mesolimbicdopaminergic reward pathways

Acetylcholine and Drugs

The most common use of anticholinergic drugs inpsychiatry is in treatment of the motorabnormalities caused by the use of classicantipsychotic drugs (e.g., haloperidol).

The efficacy of the drugs for that indication isdetermined by the balance between acetylcholineactivity and dopamine activity in the basalganglia.

In healthy people, the activity of thenigrostriatal dopamine pathway is partiallybalanced by the activity of cholinergicpathways in the basal ganglia.

Blockade of D2 receptors in the striatumupsets this balance, but the balance canbe partially restored, albeit at a lower setpoint, by antagonism of muscarinicreceptors

Blockade of those receptors leads to the

commonly seen adverse effects of blurred vision,

dry mouth, constipation, and difficulty in initiating

urination.

Excessive blockade of CNS cholinergic

receptors causes confusion and delirium.

Drugs that increase cholinergic activity by

blocking breakdown by acetyl cholinesterase

(e.g., donepezil ) have been shown to be effective

in the treatment of dementia of the Alzheimer's

type

Acetylcholine and

Psychopathology

The most common association with

acetylcholine is dementia of the Alzheimer's

type and other dementias

Acetylcholine may also be involved in mood and

sleep disorders.

CONCLUSION

Neurotransmission is the communication

b/w genomes of two neurons, through

signal transduction cascade, leading to

gene activation & biological response.

Understanding neurotransmitters, their

receptor partners & other near/distant

relations (transporters & transduction), is

essential for our approaches to define &

treat psychiatric disorders.

•Exploring the physiological & genetic basis of

neurotransmitter function may pave the way in

understanding psychopathology & nosology.

•Future researches clearly have potential to

further advance our knowledge in areas of

psychopathology, pharmacotherapy &

pharmacogenomics.

REFERENCES

1. KAPLAN AND SADDOCK’S COMPREHENSIVE TEXTBOOK OF

PSYCHIATRY. 9th ed.

2. STAHL’S ESSENTIAL PSYCHOPHARMACOLOGY:

NEUROSCIENTIFIC BASIS AND PRACTICAL APPLICATIONS. 4th ed.

3. GUYTON & HALL PHYSIOLOGY 12th ed.

4. NEUROSCIENCE ONLINE LECTURE BY Jack C. Waymire, Ph.D.,

Department of Neurobiology and Anatomy, The UT Medical School at

Houston

5. KAPLAN & SADDOCKS SYNOPSIS OF PSYCHIATRY 10th ed.