NPP Acetylcholine

Acetylcholine

a neurotransmitter in the cholinergic system

acetylcholine in the PNS

its at he neuromuscular junctions elicits that voluntary movement

acetylcholine in the CNS

it works as a strong neuromodulator

what is acetylcholine (ACh) neuromodulation? 

it alters neuronal excitability, changes neuronal firing, influences synaptic transmission, and promote synaptic plasticity.

Where is ACh synthesized in the brain?

basal forebrain nuclei and midbrain nuclei

the effects of ACh

it plays an essential role in helping concentration, memory, and cognition as well as muscle functions. 

ACh synthesis

its formed from choline and acetyl coenzyme a (acetyl CoA)

what is the rate of synthesis controlled by?

availability of precursors (choline and aCoA) and firing frequency of cholinergic cells. 

The importance of ChAT

It’s only found in neurons that use ACh as a neurotransmitter. This specificity allows the identification of cholinergic neurons by staining for ChAT

ChAT drugs? 

There are no selective inhibitors for it. Large doses of the precursor (choline) are ineffective in treating Alzheimer’s disease.

ACh storage into vesicles

It is stored in presynaptic vesicles and its moved through vesicular ACh transporters (VAChT)

How can VAChT be blocked? 

through vesamicol to reduce ACh availability for release when neurons are active. 

how is ACh released?

exocytosis

black widow spider venom

causes massive ACh release in PNS. the PNS overactivity causes muscle pain, tremors, nausea, vomiting, salivation, and excessive sweating.

botulinum toxin

An anaerobic bacterium that inhibits ACh release and is deadly due to muscular paralysis.

how is botulinum toxin used? 

at very low concentrations, it can be used to treat disorders characterized by involuntary muscle contraction. botox is localized paralysis. 

acetylcholinesterase (AChE)

it controls ACh levels through ACh breakdown to choline and acetic acid.

choline transporter

after ACh is broken down, most of the choline in the cleft is taken back to the presynaptic terminal by it. 

what blocks choline transporters and what happens? 

They are blocked by. hemicholinium-3 (HC-3)  and the effect of blocking the transporters can result in a reduction in ACh synthesis. 

AChE inhibitors

They prevent ACh breakdown, thus increasing postsynaptic effects. This can be beneficial for disorders in which cholinergic transmission is deficient. they can be toxic or even fatal. 

medicinal AChE inhibitors effects 

it depends on whether these compounds cross the BBB or where they block AChE reversibly or irreversibly.

how to use AChE inhibitors

to treat mild to moderate alzheimers disease in which there is loss of forebrain ACh neurons. increasing the availability of the remaining ACh offers some cognitive benefits.

physostigmine (Eserine)

An AChE inhibitor that crosses the BBB and affects the CNS. it can treat glaucoma if applied to the eye. 

nesostigmine/pyridostigmine

synthetic analogs of that do not cross the BBB, and thus have no actions in the CNS. it can treat myasthenia

striatum

• This brain region has ACh-producing cholinergic interneuron populations.

•  Important for regulation of movement, via interactions with dopamine (DA).

• In Parkinson’s, DA is low which results in motor symptoms.

main brain regions containing cholinergic neurons

midbrain nuclei and basal forebrain nuclei

basal forebrain cholinergic system

the origin of cholinergic innervation to the cerebral cortex, hippocampus, and other limbic system structures. Role in attention and other cognitive functions via interactions with the prefrontal cortex. 

the basal forebrain to the prefrontal cortex (BFCS →PFC)

facilitate the processing of sensory cues

nicotinic receptors

respond to the agonist nicotine. They are ionotropic and mediate excitatory responses in both the CNS and PNS. they deoplarize. 

muscarinic receptors

responds to muscarine. they are metabotrobic

when ACh binds to a nicotinic receptor….

The channel opens up, thus allowing flow of Na+ and Ca2+ into neural or muscle cells, which leads to depolarization (excitation)

succinylcholine

nicotinic antagonist, muscle relaxant.

methcamylamine

nicotinic antagonist, antihypertensive agent.

D-tubocuranine

muscle nicotinic antagonist; main ingredient of Curare, paralytic during anesthesia.

when ACh binds to a muscarinic receptor….

Another mechanism of action is stimulation of potassium (K+) channels, thus leading to hyperpolarization of cell membranes and reduction of cell firing

M1 receptor

its neural = CNS brain 

M2 receptors

Cardiac = heart, parasympathetic stimulation slows down heart rate

M3 receptors

glandular/SM = smooth muscle for contraction and exocrine glands for salivation and lacrimation

muscarine receptor antagonist

muscarine

muscarinic receptor antagonist

atropine.

atropine

used in ophthalmology to dilate pupils, reduce secretions that clog airways, and to counteract poisoning by cholinergic agonists