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Neuropharmacology: Quick Reference

Page 1: General aspects of neuropharmacology

Key processes in synthesis, storage and release of amine and amino acid transmitters:

  • Uptake of precursors

  • Synthesis of transmitter

  • Uptake/transport of transmitter into vesicles

  • Degradation of surplus transmitter

  • Depolarisation by propagated action potential

  • Influx of Ca^{2+}} in response to depolarisation

  • Release of transmitter by exocytosis

  • Diffusion to postsynaptic membrane

  • Interaction with postsynaptic receptors

  • Inactivation of transmitter

  • Reuptake of transmitter or degradation products by nerve terminals

  • Uptake of transmitter by non-neuronal cells

  • Interaction with presynaptic receptors

Transporters (11 and 12) can release transmitter under certain conditions by working in reverse. These processes are well characterised for many transmitters (e.g. ACh, monoamines, amino acids, ATP). Peptide mediators differ in that they may be synthesised and packaged in the cell body rather than terminals.

Page 2: Acetylcholine (Ach) and noradrenaline (NA) in the peripheral nervous system

Key points:

  • Receptors: nicotinic (nAChR) and muscarinic (mAChR) acetylcholine receptors

  • In the peripheral nervous system, Ach acts at synapses and neuroeffector junctions to mediate fast signaling.

Page 3: Cholinergic and noradrenergic transmission

Cholinergic pathway:

  • Acetyl-CoA + Choline → (via choline acetyltransferase, ChAT) ACh

  • Choline reuptake blocked by hemicholinium; vesicular uptake blocked by vesamicol; release of ACh; breakdown by acetylcholinesterase (AChE) inhibitors prolong action

  • Postsynaptic receptors: Nicotinic (ionotropic) and Muscarinic (GPCR) with subtypes: M1, M3, M5 (excitatory) and M2, M4 (inhibitory)

Noradrenergic pathway:

  • Tyrosine → DOPA (tyrosine hydroxylase)

  • DOPA → Dopamine (DOPA decarboxylase)

  • Dopamine → NE (dopamine-β-hydroxylase)

  • Packaging into vesicles via VMAT; reuptake via NET; synaptic NE acts on postsynaptic adrenergic receptors; inactivation by MAO (and COMT)

  • Autoreceptors: β1/β2 on presynaptic membrane regulate release

Key transport and degradation terms: VMAT, NET, MAO, AChE.

Page 4: The main autonomic effects

The main co-transmitters at postganglionic parasympathetic and sympathetic neurons can evoke fast, intermediate and slow responses in target organs. Mediators include: ACh, ATP, NA, NO, NPY, VIP.

  • peptides are not produced in the terminal / nerve ending, rather in the cell body, then transported down.

Page 5: Presynaptic regulation of transmitter release from noradrenergic and cholinergic nerve terminals

[A] Postulated homotropic and heterotropic interactions between sympathetic and parasympathetic nerves.

[B] Known inhibitory and facilitatory influences on NA release from sympathetic nerve endings:

  • 5-HT, adrenaline, ACh, NA, NO, PG, PGE

  • The enteric nervous system also contributes to regulation.

Page 6: Co-transmission and neuromodulation — some examples

[A] Presynaptic inhibition (autoinhibitory feedback by NA and Ach).

[B] Heterotropic presynaptic inhibition (e.g., vagus nerve – parasympathetic, cholinergic, negative heart effect; sympathetic nerve – noradrenergic, positive heart effect).

[C] Postsynaptic synergism. Mediators include: ACh, ATP, GnRH, NPY, SP (substance P), VIP.

Page 7: Generalised diagram of a noradrenergic nerve terminal and amphetamine action

Sites of drug action include EMT (extraneuronal monoamine transporter), MAO (monoamine oxidase), MeNA, NA, NET (neuronal norepinephrine transporter).

Amphetamine mechanism:

  • Enters nerve terminal via NET and then into synaptic vesicles via VMAT, exchanging for NA which accumulates in the cytosol.

  • Some NA is degraded by MAO within the terminal; some escapes via NET to act on postsynaptic receptors.

  • Amphetamine also reduces NA reuptake via NET, enhancing the action of released NA.