Catecholamines Stored in vesicles Release tightly controlled Presynaptic receptors Activators include NE (  2 ), DA (D 2 ), 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) VMAT 1 found in adrenal medulla VMAT 2 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 2 nd messenger system Receptors may down-regulate in presence of antidepressant drugs which inhibit re-uptake (eg maprotilene, bupropion)

Receptor types: Dopamine Dopamine 5 subtypes D 1 – D 5 D 1, D 5 similar D 2, D 3, D 4 separate family D 1 and D 2 most common Found in: striatum (basal ganglia) and nucleus accumbens (limbic)

D 1, D 2 have opposite effects: activate different G proteins (G s, G i) Also, D 2 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 D 1 receptor effect  2 similar to DA D 2 receptor effect (commonly an autoreceptor)  1 operates through phosphoinositide 2 nd messenger system  Ca 2+ influx within postsynaptic cell (G q )

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) LC  2 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-HT 1A Terminal autoreceptors 5- HT 1B or 5-HT 1D

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-HT 1 large family: 5-HT 1A, 5-HT 1B ……etc Smaller 5-HT 2 family 5-HT 2A, 5-HT 2B ……etc : Plus 5-HT 3, 5-HT 4, 5HT 5, 5-HT 6, 5-HT 7 All metabotropic (class II), except 5-HT 3 – excitatory ionotropic receptor

5-HT 1A Receptor: hippocampus, septum, amygdala, raphe nuclei (G i ) 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-HT 2A Receptor: large numbers in cerebral cortex, also striatum, nucleus accumbens (G q ) activates phosphoinositide 2 nd 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-HT 2A receptor stimulation Antagonists: ketanserin, ritanserin

Acetyl Choline HC-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 M 1 – M 5 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 GABA A Ionotropic: opens chloride channels Classic agonist = muscimol Macroscopia Hyperthermia Pupil dilation Elevation of mood Difficulties with concentration Anorexia Catalepsy, hallucinations

GABA A Antagonist Bicuculline – best known competitive antagonist Convulsant Pentylenetetrazol, picrotoxin Non competitive convulsants

GABA A sensitivity to CNS depressant drugs Benzodiazepines (BDZs), barbiturates, Potentiates the action of GABA on GABA A Receptors on GABA A for other ligands Eg BDZ (diazepam = valium) “sensitises” the receptor to GABA BDZs cannot activate the GABA A receptor on their own No effect in the absence of GABA

GABA B Metabotropic receptor Inhibition of cAMP K + opening GABA B agonists/antagonists have no effect on GABA A GABA B activated by selective agonist baclofen (Lioresal) Muscle relaxant, anti-spastic agent