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Catecholamines

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

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Catecholamines

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  1. 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

  2. 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

  3. Reserpine 5mg kg-1 Plus DOPA 200mg kg-1 (Carlssen et al 1957)

  4. MAO Mono amine oxidase; COMT catechol-O-methyltransferase MOA inhibitors COMT inhibitors Eg Phenelzine, tranylcypromine Entacapone Tolcapone DAT; 5-HTT (or SERT), NAT, NET Transport blocking drugs: Cocaine - DA, - NE, - 5HTT Reboxetine -NE; tricyclic antidepressants –NE, -5HTT

  5. 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)

  6. 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)

  7. D1, D2 have opposite effects: activate different G proteins (Gs, Gi) Also, D2 activates G protein that opens K+ gates

  8. Dopamine Pathways I • substantia nigra (mesencephalon) • basal ganglia • Role in movement control • Parkinsonism • Antipsychotic-induced extra-pyramidal side effects NIGROSTRIATAL DA PATHWAY

  9. 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

  10. 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)

  11. The Locus Coeruleus

  12. LC and Vigilance Aston Jones 1985

  13. Effect of 1 and  adrenergic agonists injected into the rat medial septum on time spent awake Berridge et al 2003)

  14. 2 receptor: effect blocked by 2 antagonist (eg yohimbine) and mimicked when 2 agonist (eg clonidine) replaces NE LC (Wellman et al 1992)

  15. 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

  16. More similarities…….. • Release directly stimulated by amphetamine-type drugs • Para-chloramphetamine • fenfluoramine • 3,4-methylenedioxymethamphetamine (MDMA – ecstasy)

  17. 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)

  18. 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

  19. “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

  20. 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

  21. 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

  22. 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

  23. Acetyl Choline HC-3 hemicholinium AChE blocked by (eg) Physostigmine, Neostigmine Insecticides (malathion) Nerve gas (sarin, soman)

  24. Ach central pathways Note: basal forebrain cholinergic system (BFCS)

  25. Ach Receptors • Two families • Nicotinic • Ionotropic, 5 subunits, • Muscarinic • Metabotropic • M1 – M5 • Agonists: (parasympathomimetic) eg pilocarpine • Antagonists: (parasympatholytic) eg atropine, scopolamine

  26. Glutamate: excitatory amino acid

  27. Glutamate receptors (and kainate) MGluR1- MGluR8 Phencyclidine, ketamine

  28. 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

  29. Gamma Amino Butyric Acid

  30. GABA Receptors • GABAA • Ionotropic: opens chloride channels • Classic agonist = muscimol • Macroscopia • Hyperthermia • Pupil dilation • Elevation of mood • Difficulties with concentration • Anorexia • Catalepsy, • hallucinations

  31. GABAA Antagonist • Bicuculline – best known competitive antagonist • Convulsant • Pentylenetetrazol, picrotoxin • Non competitive convulsants

  32. 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

  33. 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

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