PSYC 462: Acetylcholine

where does ACh synthesis take place?

peripheral and central NS, including parasympathetic NS

what is acetylcholine synthesized from?

choline + acetyl CoA

ChAT

enzyme that synthesizes ACh

what enzyme is responsible for synthesizing ACh?

ChAT

regulation of ACh synthesis depends on…

• availability of precursors

• neuron firing rate

ChAT inhibitor - drug name

drug does not exist! we cannot selectively block ACh synthesis

ACh is packaged by…

vesicular ACh transporter (VAChT)

vesamicol function

• blocks VAChT

  • so, ACh cannot enter vesicles

• reduces ACh storage

toxins that affect ACh release

• black widow spider venom

• botulinum toxin

black widow spider venom - effects

• causes massive ACh release

• excessive parasympathetic symptoms (secretions, muscle pain, tremor, nausea, salivation, etc.)

botulinum toxin - effects

• inhibits ACh release at NMJ

• muscle paralysis

• leads to respiratory failure if it affects the diaphragm

is ACh reuptaken directly?

NO - is broken down by AChE instead

ACh is broken down by…

acetylcholinesterase (AChE)

ACh breakdown products

choline and acetate

ACh breakdown - procedure

• rapidly broken down by AChE

  • produces choline + acetate

• choline is recycled back into the neuron

hemicholinum-3 (HC-3) function

blocks choline transporter from being recycled back into neuron

• this reduces ACh synthesis

drugs that affect ACh degradation

• HC-3

• physostigmine

• irreversible AChE inhbitors, eg:

  • some insecticides

  • nerve gases (eg: Sarin)

physostigmine - function

• crosses BBB and inhibits AChE

• this increases ACh levels

• used in Alzheimer’s - early cognitive benefit

examples of irreversible AChE inhibitors

• some insecticides

• nerve gases, eg: Sarin

irreversible AChE inhibitors results in…

excessive ACh release, leading to muscle paralysis and eventually death

nicotinic ACh receptors - ionotropic or metabotropic?

ionotropic

characteristics of nicotinic receptors

• ligand-gated ion channels

• allow influx of Na+ and Ca2+

• cause rapid depolarization and fast, excitatory responses

structure of nicotinic receptors

• 5 subunits - a combination of alpha, beta, gamma, delta, epsilon

  • these subtypes differ in affinity, kinetics, binding sites

what happens during nicotinic overactivation

1. desensitization (receptor-level)

2. depolarization block (membrane-level)

desensitization of nicotinic receptors

• receptors desensitize

• channels remain closed, even if an agonist is bound

• receptors take a break, and then recover after a short time with no stimulation

depolarization block - nicotinic receptors

• prolonged activation = persistent depolarization

• resting membrane potential is lost - too much ion flux in/out, cannot maintain Na+/K+ homeostasis

• voltage-gated channels cannot reset and neurons cannot generate APs

  • cell cannot excite until membrane repolarizes and the agonist is removed

succinylcholine effects

• a nicotinic agonist, resistant to AChE breakdown

• produces a depolarization block and is used as a muscle relaxant during surgery

list of nicotinic agonists

• succinylcholine

• partial agonists*

list of nicotinic antagonists

• mecamylamine

• D-tubocurarine

mecamylamine function

block nicotinic receptors in both CNS and autonomic ganglia

D-tubocurarine function

• blocks muscle nicotinic receptors

• does not respond to CNS well (doesn’t cross BBB)

• paralysis, used in hunting - tipped in blowdarts

partial agonist function

• cognitive enhancer

• nicotine addiction - preferentially targets craving aspect

muscarinic receptors - ionotropic or metabotropic?

metabotropic

how many subtypes of muscarinic receptors

M1-5

muscarinic receptors mechanism

act via 2nd messengers, enhancing K+ channel openings

which muscarinic receptors are present in the CNS?

M1, 4, and 5

M2 receptor location/function

• heart - slow heart rate

• brain - presynaptic terminal autoreceptor in CNS

M3 receptor location/function

• smooth muscle

  • for contraction/digestion, secretory responses

list of muscarinic receptor agonists

pilocarpine

pilocarpine function

cause parasympathetic overactivation

• symptoms: SLUDGE

  • salivation, lacrimation, urination, diarrhea, gastrointestinal issues, emesis

list of muscarinic receptor antagonists

• atropine

• scopolamine

atropine and scopolamine functions

• block parasympathetic effects

  • dilate pupils, reduce secretions that clog airways, treat cholinergic poisoning

atropine and scopolamine side effects

• dry mouth

• memory impairment

• reduced REM sleep

• drowsiness, fatigue

basal forebrain cholinergic system (BFCS) projects to..

• cortex

• hippocampus

• limbic structures

BFCS is critical for which functions?

• memory

• attention

• cognitive function

  • lesions impair attention and memory

list of key ACh cell groups

• BFCS

• striatum

• dorsolateral pons

striatum - characteristics

• contains cholinergic interneurons

• balance between DA and ACh

  • Parkinson’s - not enough DA, too much ACh

what can we use as early treatment for Parkinsons?

muscarinic antagonists

• they reduce ACh levels, restoring balance between ACh and DA

dorsolateral pons projects to…

midbrain DA neurons

ACh in the dorsolateral pons regulates…

• burst firing

• reinforcement mechanisms

  • is involved in addictive effects of nicotine

what does AChE normally do - PNS

rapidly breakdown ACh into choline and acetate to terminate signalling

what happens when AChE is blocked - PNS

ACh accumulates → excessive stimulation of cholinergic synapses

excess ACh (eg: AChE inhibition) leads to…

• muscle overstimulation

• excess secretions

• autonomic overactivation

• depolarization block → paralysis

examples of AChE inhibitors

• physostigmine (reversible)

• nerve gases (irreversible)

what does vesacimol do?

block VAChT → prevent ACh from entering vesicles → reduced ACh storage

what does HC-3 do?

block choline transporter → reduce ACh synthesis

effects of reduced ACh (via vesamicol, HC-3)

• decreased cholinergic transmission

• reduced peripheral signalling

• cognitive deficits

which brain system is critical for ACh and attention

basal forebrain cholinergic system (BFCS)

what does the signal detection task test?

attention: the ability to detect brief stimuli and maintain stimuli

• rat press 1 lever if they see the light, press another if they don’t

what happens to corticla ACh during attention tasks

ACh in frontal cortex increases during attention-demanding tasks

what do BFCS lesions (192IgG-saporin) show?

• impaired performance on attention tasks

• reduced ability to detect signals

• confirms ACh is necessary for sustained attention

what happens to cortical ACh during attention tasks?

ACh in frontal cortex increases during attention-demanding tasks