acetylcholine

Question 1

ACh function in PNS

Answer 1

used at all neuromuscular junctions and parasympathetic nervous systeml used to move

Question 2

ACh function in CNS

Answer 2

multiple cell body regions enervate cortical / subcortical regions and ACh interneurons in the stratum

Question 3

ACh is made from

Answer 3

Choline and acetyl coenzyme A (acetyl CoA), catalyzed by choline acetyltransferase (ChAT) (which is only in neurons that use ACh

Question 4

rate of ACh synthesis is controllled by

Answer 4

availability of precursors (get both choline and acetyl CoA from die), rate of cell firing (upregulation for frequent)

Question 5

ways to target ACh levels

Answer 5

cannot inhibit synthesis - no selective inhibitors of ChAT yet
can target packaging
can target degredation (no direct reuptake)

Question 6

ACh packaging

Answer 6

ACh packaged into vesicles via vesicular ACh transporters (VAChT), can be inhibited with vesamicol

Question 7

ACh release

Answer 7

can be ^ massively with black widow spider venom(in PNS) and inhibited by botulism toxin (at neuromuscular junctions)

Question 8

vesamicol:

Answer 8

blocks VAChT, reduces ACh levels

Question 9

black widow spider venom

Answer 9

causes massive ACh release in PNS: cholinergic overactivity causes muscle pain, tremors, nausea, vomiting, salivation, copious sweating

Question 10

botulism toxin

Answer 10

actually trumps black widow venom (locally)
inhibits ACh relase selectively in neuromuscular junction, inhibition of cholinergic activity can be deadly because of muscular paralysis

Question 11

acetylcholine degredation

Answer 11

levels controlled by acetycholinesterase (AChE), they are stuck to closeby postsynaptic membranes, rapidly breaks down ACh into choline9recycled) and Acetic acid

Question 12

hemicholinium-3 (HC-3)

Answer 12

blocks choline transporters, reduces rate of ACh production (by blocking the choline recycled at the terminal)

Question 13

blocking AChE (Ach inactivation) causes

Answer 13

increase in postsynaptic effects of the transmitter;
weak version: pesticide
strong version: nerve gas (like Sarin) (antidote is probably going to be cholinergic antagonists that block the excess cholinergic effects)
other pharmacological use: physostigmine: crosses BBB and offset some cognitive decline associated with Alzheimers

Question 14

physostigmine:

Answer 14

crosses BBB (works in periphery AND brain), increases Ach essentially, useful for Alzheimers (because you’re losing cholinergic neurons in the brain)

Question 15

2 postsynaptic acetycholine receptors

Answer 15

nicotinic receptor and muscarinic receptors

Question 16

nicotinic receptors

Answer 16

• responds to nicotin; ligand gated ion channels; allows sodium and calcium to enter the cell and depolarize; similiar to AMPA;
  continuous activation fo nicotinic receptors 1) initially causes desensitization (closed channels even with bond agonist), recovers after a short time with no stimulation, and 2)prolonged activation leads to epolarization block - persistent depolarization causes resting potential to be lost; cell can’t be excited until agonist is removed and membrane repolarizez

Question 17

nicotinic agonists

Answer 17

succinylcholine; muscle relaxant - resistant to breakdown by AchE (depolarization block), locally used for surgical procedures

Question 18

nitonitic antagonists

Answer 18

mecamylamine: blocks nicotinic receptors both in CNS and autonomic ganglia; antidote for nicotine poisoning
D-tubocurarine: blocks muscle nicotinic receptors; relatively little effect on CNS, low BBB passing; paralyses for hunting

Question 19

nicotinic partial antagonists

Answer 19

selective to particular pathways, like DA system (for quitting smoking)

Question 20

muscarinic receptors - responds to muscarine

Answer 20

all metabotropic, 5 main subtypes; all found in brain; not all inhibitory, operate via second messengers and/or enhance K+ channel opening

Question 21

M2 receptors

Answer 21

PNS: cardic; slows heart rate when activated, but also act as presynaptic autoreceptor in CNS

Question 22

M3

Answer 22

on smooth muscles (PNS), activation results in contraction of digestive tract and ++fluids (rest and digest)

Question 23

muscarinic agonists

Answer 23

pilocarpine: parasympathomimetic agent; leads to SLUDGE: exaggerated parasympathetic responses

Question 24

SLUDGE

Answer 24

Salivation, Lacrimation, Urination, Diarrhea, Gastrointestinal distress, and Emesis (vomiting); exaggerated parasympathetic responses, overactivation of M3

Question 25

muscarinic antagonists

Answer 25

atropine and schopolamine; inhibit parasympathetic effects; similar to activation of sympathetic nervous system (aka antidote to nerve gasses); will cross BBB - leading to drowsiness, euphoria, amnesia, fatigue, and dreamless sleep (no REM)

Question 26

3 key clusters for ACh

Answer 26

stiatum, dorslolateral pons, Basal forebrain cholinergic system (BFCS)

Question 27

straitum and ACh

Answer 27

contains cholinergic interneurons; regulation of movement depends in part on balance between Ach and dopamine; low DA in parkinson (cell loss in substantia nigra) can be somewhat balances by lowering ACh (muscarinic antagonists like schopolamine and atropine) (same as L-DOPA in some sense)

Question 28

dorsolateral pons and Ach

Answer 28

2 distinct nuclie send long axons to middle parts of brain; send axons to DA neurons in VTA;ACh in this area is usually excitatory and will do burst patterns of firing (more NT release); probably useful for attention and alertness, also drugs of abuse

Question 29

BFCS and Ach (bottom front part of brain)

Answer 29

send axons to front part of brain; emotional regulation and different types of cognitive functions; when disrupted, impairment in memory and cognitive functiong, but most importnat for attention (cue signal detection task)

Question 30

tell me abiout the flashing light / attention experiment

Answer 30

There a signal trials, where a light is flashed, and non-signal trials, where no light is flashed
Levers will appear in front of the rat and the rat needs to choose the left lever if they saw the light or press the right lever if they didn’t
Correct answers will grant them a reward

1. This activity requires attention, and we observe that ACh in frontal cortex increases when the rats are performing this task. The researchers also did control experiments where the rat is pressing lever for food or doing signal/non-signal trials that don’t require attention (eg. the light stays on/off the entire trial) - in these situations, ACh release is less. Thus, increased ACh release does seem to be correlated with increased attention/performance on task.
2. However, since study 1 is merely correlational, they also did a lesion study where they selectively destroyed basal forebrain cholinergic neurons using 192 IgG-saporin which impaired performance. We know that their impairment in performance is not due to the rats randomly responding because their “correct rejections” were not impaired.
3. Finally, researchers used more discrete optogenetic manipulations of these basal forebrain cholinergic cells. They used viral vectors to insert different opsins that can either stimulate or suppress firing of cholinergic neurons within the basal forebrain cholinergic systems. In the really short signal lengths where animals tend to perform poorly, if you stimulate cholinergic neurons, animals perform a lot better. On the other hand, if you inhibit the firing of the cholinergic neurons when the longer signal is going on, they perform worse.