2.7 - Acetylcholine, Nicotine, and Muscarine

Acteylcholine (ACh)

- major NT at NMJ and ANS, acts as NT and neuromodulator in CNS

cholinergic agonists

- nicotine = toxic stimulant from Solanaceae

- Muscarine = convulsant A. muscaria

ACh synthesis

- acetylation of choline at -OH catalyzed by choline acetyltransferase (ChAT)

- consumes Acetyl coenzyme A

- availability of choline = limiting step

choline

- obtained from diet, used in cell membrane synthesis

- N+ prevents passage = take up via Na+ cotransport via choline transporter (CHT1)

vesicular ACh transporter

uses co-transport to exchange pumped H+ for ACh

ACh metabolism

- AChE converts ACh into choline and acetate

- AChE is abundant in synaptic cleft; works fast

Ach Normal function

ACh nerve agent

nAChR

- ACh gated ion channel (↑ Na+influx, K+ efflux, and Ca2+ influx); excitatory

- depolarizes fast, non-selective cation channel

- composed of 5 subunits forming pentameric channel w/ pore

- composition dictates drug affinity, Ca2+ permeability, and kinetics

mAChR

ACh-metabotropic GPCR; five different types f(x) varies

M1 (mAChR receptor)

excitatory, Gq-linked; ↑ PLC, ↑IP3 and DAG

M2 (mAChR receptor)

inhibitory, Gi-linked; ↓ AC and cAMP

M3 (mAChR receptor)

excitatory, Gq-linked; ↑ PLC, ↑ IP3 and DAG

M4 (mAChR receptor)

inhibitory, Gi-linked; ↓ AC and cAMP

M5 (mAChR receptor)

excitatory, Gq-linked; ↑ PLC, ↑ IP3 and DAG

Type (alpha7)5 nAChR

- passes Na+, K+, and Ca2+

- mediates pro-cognitive effect

Type (alpha4)2(beta4)3 nAChR

- passes Na+ and K+

- mediates rewarding effects

Short interneurons in caudate/putamen

- regulate motor output (respond to environment to establish motor response)

- inhibited by dopamine neurons of substantia

Parkinson’s

loss of DA inhibition causes excess ACh → resting tremors

Pontomesencephalotegmental complex

- cholinergic cell bodies in brain stem (pedunculopontine nucleus + laterodorsal tegmental nucleus)

- activity mediated by M1AChR

- increases autonomic outflow; increases secretions

- regulates pain = M2 and M4; ↓ pain through nociceptor inhibition

AChE inhibtors

↑ ACh = ↑ analgesia

Basal forebrain

- cholinergic cell bodies originate from basal optic nucleus of Meynert and septal nucleus

- major brain ACh system = regulates and modulates MOST systems

neuromodulation

AChR auto receptors decrease NT release