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Neuroscience 4 – Neurochemistry Anil Chopra 1. Outline the course and function of the 3 diffuse monoaminergic pathways in the brain. 2. List the main 5-HT and dopamine receptors and give examples of drugs that modify their action. There are 3 main types of Neurotransmitter system: Long axon systems – Corticospinal tract (Glutamate) Short axon intrinsic systems (GABA) Controlling systems – divergent (monoamines) Neurotransmitters NA, ACh (ANS) Glu, GABA Monoamines (NA, 5-HT, DA) Noradrenaline Biosynthesis & Release: Tyrosine Tyrosine hydroxylase DOPA DOPA decarboxylase Tyrosine Dopamine Dopamine Dopamine hydroxylase Noradrenaline Metabolites Monoamine oxidase A (MAO-A) Noradrenaline Action potential Uptake 1 Noradrenaline Ca++ Uptake 2 Noradrenaline Adrenoceptor Noradrenaline Pathways Cell body clusters: pons & medulla i) Locus coeruleus (LC) ii) Reticular formation (RF) These are nuclei where noradrenalin is synthesised. Functional aspects of Noradrenaline • • NA usually inhibitory (β-receptors) Normally has excitatory action (α1/β1 receptors) Regulation of BP • • • Central and peripheral NA systems Clonidine reduces the production of noradrenalin by binding to α2 receptors. (baroreceptor reflex pathway) This therefore makes clonidine useful as an anti-hypertensive drug. [Ca2+ antagonists, ACE inhibitors etc] Arousal & mood LC (locus coeruleus) activity is associated with behavioural arousal and mood. NA deficiency depression NA excess mania Amphetamines increase wakefulness + alertness LC neurons are the site of NA release and increase NA release in times of stress. Many antidepressant drugs target the neurones to increase NA-ergic transmission e.g. MAOIs (monoamine oxidase inhibitors) and TCAs (tri-cyclic antidepressants). 5-HYDROXYTRYPTAMINE (5HT) NB – also known as serotonin. 5HT Pathways • • • • • Distn widespread; similar to NA Cell body clusters: pons & upper medulla It is released from the raphe nuclei. Rostral ascending pathways (MFB) Caudal descending pathways Functional aspects of 5 –Hydroxytryptamine a) • • b) Hallucinatory effects Centrally acting 5HT analogues have been know to be hallucinogenic (LSD) Firing brainstem 5HT neurons cortical inhibition ? hallucinations Sleep, wakefulness & mood • • Raphé nuclei activity sleep Raphé nuclei lesions sleep abolition 5HT precursors are often the target of insomnia treatment (tryptophan; 5hydroxytryptophan) • • • • • MA theory of depression: 5HT Currently used antidepressant drugs: inhibit 5HT breakdown: MAOIs inhibit 5HT re-uptake TCAs (tricyclic antidepressants); SSRI’s (selective serotonin reuptake inhibitor) Subtype-selective 5HT receptor agonists Dopamine Pathways