Catecholamines Stored in vesicles

Release tightly controlled

Presynaptic receptors Activators include

NE (2), DA (D2), Ach, prostaglandins,

other amines, glutamate and/or

endorphins

Autoreceptors important target for

antidepressant drugs eg mirtazapine

Amphetamines can stimulate

release of stored catecholamines Behavioural activation

Vesicular Packaging

Vesicular monoamine transporter (VMAT)

VMAT1 found in adrenal medulla

VMAT2 found in brain

Both blocked by reserpine Elevated intracellular breakdown of DA and NEebox

Low levels in brain

Sedation in animals, depressive symptoms in

humans

Plus DOPA 200mg kg-1

Reserpine

5mg kg-1

(Carlssen et al 1957)

DAT; 5-HTT (or SERT), NAT, NET

MAO Mono amine oxidase; COMT catechol-O-methyltransferase

MOA inhibitors

Transport blocking drugs: Cocaine - DA, - NE, - 5HTT

Reboxetine -NE; tricyclic antidepressants –NE, -5HTT

Eg Phenelzine,

tranylcypromine

COMT inhibitors

Entacapone

Tolcapone

Post Synaptic Catecholamine Receptors

Class 2; Metabotropic; GPCR

Open ion channels and/or influence

metabolism by 2nd messenger system

Receptors may down-regulate in

presence of antidepressant drugs which

inhibit re-uptake (eg maprotilene,

bupropion)

Receptor types: Dopamine

Dopamine

5 subtypes D1 – D5

D1, D5 similar

D2, D3, D4 separate family

D1 and D2 most common

Found in: striatum (basal ganglia) and nucleus

accumbens (limbic)

D1, D2 have opposite effects: activate different G proteins (Gs, Gi)

Also, D2 activates G protein that opens K+ gates

Dopamine Pathways I substantia nigra

(mesencephalon)

basal ganglia

Role in movement

control

Parkinsonism

Antipsychotic-induced

extra-pyramidal side

effects

NIGROSTRIATAL DA PATHWAY

Dopamine Pathways II

Midbrain (VTA10) near

substantia nigra

cerebral cortex (esp.

frontal cortex)

limbic system (esp.

limbic cortex, nucleus

accumbens, amygdala,

hippocampus

Underlies reward

system

MESOCORTICAL

MESOLIMBIC

Noradrenaline Receptor Types

Norepinephrine (and epinephrine) exert effects via two

primary types: , adrenoreceptors

each has two subtypes 1, 2; 1, 2

1, 2 similar to DA D1 receptor effect

2 similar to DA D2 receptor effect (commonly an

autoreceptor)

1 operates through phosphoinositide 2nd messenger

system Ca2+ influx within postsynaptic cell (Gq)

The Locus Coeruleus

LC and Vigilance

Aston Jones 1985

Effect of 1 and adrenergic agonists injected into the rat medial septum on time spent awake

Berridge et al 2003)

(Wellman et al 1992)

LC2 receptor: effect blocked by 2 antagonist (eg

yohimbine) and mimicked when 2 agonist (eg

clonidine) replaces NE

Serotinin: 5-hydroxytryptamine (5-HT)

“Serotonergic neurones”

Same VMAT2

VMAT2 blocker reserpine

depletes 5HT

Serotonergic autoreceptors

Somatodendritic 5-HT1A

Terminal autoreceptors 5-

HT1B or 5-HT1D

More similarities……..

Release directly stimulated by

amphetamine-type drugs Para-chloramphetamine

fenfluoramine

3,4-methylenedioxymethamphetamine

(MDMA – ecstasy)

5-HT uptake also similar

5-HT transporter Key site of drug uptake

eg Fluoxetine (Prozac)

Antidepressant

Selective serotonin reuptake inhibitors (SSRIs)

nb MDMA and cocaine interact with 5-HTT, but

not selective (also influence DA transporter)

Catabolism

DA, NE metabolised by MAO and COMT

5-HT not a catecholamine, therefore COMT not

effective

MAO + 5-HT 5-hydroxyindoleacetic acid (5-

HIAA)

Brain or CSF 5-HIAA used as a measure of

serotonergic activity

“B” 1-8: The Raphe Nuclei – in midbrain and pons

Major source of seroternergic fibres: B7 Dorsal Raphe; B8 median Raphe

To: all forebrain: neocortex, striatum, nucleus accumbens, thalamus, hypothalmus, and limbic structures – hippocampus, amygdala, septal area

5-HT receptors: horrible!

15 subtypes, so far

Including:

5-HT1 large family: 5-HT1A, 5-HT1B……etc

Smaller 5-HT2 family 5-HT2A, 5-HT2B……etc :

Plus 5-HT3, 5-HT4, 5HT5, 5-HT6, 5-HT7

All metabotropic (class II), except

5-HT3 – excitatory ionotropic receptor

5-HT1A Receptor: hippocampus,

septum, amygdala, raphe nuclei

(Gi) inhibits adenylate cyclase (cAMP

Opens K+ channels

Receptor agonists Buspirone, ipasapirone, 8-hydroxy-2-(di-n-propylamino) tetralin (8-

OH-DPAT)

Hyperphagia (5-HT tends to reduce appetite)

Reduced anxiety

Hypothermia

Inhibits motivation to drink alcohol

5-HT2A Receptor: large numbers in cerebral

cortex, also striatum, nucleus accumbens

(Gq) activates phosphoinositide 2nd messenger system

Agonists

1-(2,5 dimethoxy-4-iodophenyl)-2-aminopropane (DOI)

Hallucinogenic (cf Lysergic acid diethylamide; LSD)

Head twitch response in rats/mice

Measure of 5-HT2A receptor stimulation

Antagonists: ketanserin, ritanserin

Acetyl CholineHC-3 hemicholinium

AChE blocked by (eg)

Physostigmine, Neostigmine

Insecticides (malathion)

Nerve gas (sarin, soman)

Ach central pathways

Note: basal forebrain cholinergic system (BFCS)

Ach Receptors

Two families

Nicotinic Ionotropic, 5 subunits,

Muscarinic Metabotropic

M1 – M5

Agonists: (parasympathomimetic) eg pilocarpine

Antagonists: (parasympatholytic) eg atropine,

scopolamine

Glutamate: excitatory amino acid

Glutamate receptors

(and kainate)

MGluR1- MGluR8

Phencyclidine, ketamine

Roles AMPA (selective agonist: amino 3 hydroxy 5

methyl 4 isoxazole proprionic acid) – rapid

excitation Normal locomotor activity, motor co-ordination, learning

NMDA (N-methyl-D-aspartate) Learning, memory, cognitive ability

MGluR1 Normal cerebellum control of motor function

High levels of glutamate are neurotoxic Depolarisation-induced excitotoxicity

Gamma Amino Butyric Acid

GABA Receptors GABAA

Ionotropic: opens chloride channels Classic agonist = muscimol

Macroscopia Hyperthermia Pupil dilation Elevation of mood Difficulties with concentration Anorexia Catalepsy, hallucinations

GABAA Antagonist

Bicuculline – best known competitive

antagonist

Convulsant

Pentylenetetrazol, picrotoxin

Non competitive convulsants

GABAA sensitivity to CNS depressant drugs

Benzodiazepines (BDZs), barbiturates,

Potentiates the action of GABA on GABAA

Receptors on GABAA for other ligands

Eg BDZ (diazepam = valium) “sensitises” the receptor

to GABA

BDZs cannot activate the GABAA receptor on their

own

No effect in the absence of GABA

GABAB

Metabotropic receptor Inhibition of cAMP

K+ opening

GABAB agonists/antagonists have no effect on

GABAA

GABAB activated by selective agonist baclofen

(Lioresal) Muscle relaxant, anti-spastic agent