(From Dr. Nardell’s ANS Physiology Handout, by Brian Buschman)
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At the cholinergic junction hemicholiniums block the uptake of choline into the presynaptic nerve terminal. Vesamicol blocks the uptake of ACh into vesicles. Botulinum toxin prevents the release of ACh from the presynaptic membrane. Latrotoxin causes an explosive release of ACh.
The presynaptic membrane also has receptor sites for autoregulation if you are talking about postganglionic sympathetic neurons. There are nicotinic sites that increase ACh release and a2 and muscarinic sites that inhibit it. The sympathetic neuron exhibits presynaptic inhibition onto the parasympathetic neuron via the a2 receptors.
There are a few drugs that block the function of adrenergic terminals like metyrosine which blocks the conversion of tyrosine to L-DOPA. Reserpine will block the uptake of dopamine into vesicles. Tricyclic antidepressants block the reuptake of NE to be reused.
In the sympathetic neuron autoregulation comes from it’s NE activity back on it’s own a2 to further repress NE release. Epi can come in and cause stimulation via b2 receptors. This is an exception to the rule that b2 receptors are inhibitatory. ACh can also cause presynaptic inhibition via muscarinic receptors.
Heteroreceptors are receptors that are stimulated by a NT which causes them to regulate the release of another NT. Autoreceptors are receptors that are stimulated by a drug to regulate the release of the same drug.
Cholinergic transmission is terminated by acetlycholinesterase. Adrenergic transmission can be terminated by active reuptake by the neuron, by peripheral structures (like glia) or by diffusion to a metabolizing organ. Tricyclic antidepressants block the reuptake of NE in the presynaptic terminal.
All ganglia are nicotinic-cholinergic regardless of if they are PANS or SANS. This makes it
Nicotinics can be broken into to types:
1) Nn which are located at neuron-neuron junctions and function to open Na+ or Ca2+ channels. Nn receptors are the type that exist at the adrenal medulla since the adrenal medulla cells are modified postganglionic sympathetic neurons.
2) Nm receptors are located on skeletal muscle at the motor end plate and function by opening Na+ channels.
Nicotinics open channels which must be ligand gated because the opening is triggered by ACh.
Muscarinic receptors can be divided into three types which all function via G-proteins. Types M1 and M3 work with Gq proteins and M2 with Gi. Like we have played all along the general rule is that type 2s are inhibitatory and types 1 and 3 are stimulatory.
1) M1 receptors function in the CNS, ganglia and in parietal cells. A selective M1 blocker could decrease the output of HCl in the stomach.
2) M2 receptors function to decrease heart rate and function in presynaptic inhibition as already discussed. In general it does all of the parasympathetic jobs that involve inhibitatory neurotransmission.
3) M3 receptors function to contract smooth muscle, stimulate exocrine glands and carry out all parasympathetic stimulatory functions not associated with the CNS, ganglia or parietal cells (M1).
Hemicholiniums are a class of drugs that block the uptake of choline into cholinergic nerve terminals.
Vesamicol blocks the uptake of ACh into vesicles in the presynaptic nerve terminals.
Botulinum toxin blocks the release of ACh from the presynaptic membrane.
Latrotoxin causes an explosive release of ACh.
Physostigmine blocks ACh metabolism by acetlycholinesterase.
Muscarin activates muscarinic receptors.
Atropine blocks muscarinic receptors.
Nicotine stimulates nicotinic receptors.
Turbocurarine blocks the Nm receptors.
Trimethaphan blocks Nn receptors.
Study the table in the handout, pp 22-23.
In general it’s a normal parasympathetic response with M1 working on the parietal cells, M2 inhibiting the heart and M3 stimulating everything else. There is one exception, the cholinergic sympathetics which use cholinergic postganglionic neurons to constrict some blood vessels as part of the sympathetic response. Everything else done by cholinergic is with parasympathetic (postganglionic is muscarinic), preganglionic (nicotinic) or somatic (somatic).
There are three classes of adrenergic receptors a, b and D receptors. a and b are stimulated by NE and Epi and usually work in the sympathetic response. The D receptors are stimulated by dopamine, are mostly in the CNS and are not related to the sympathetic response. Let’s get them out of the way first.
There are at least five types of dopamine receptors:
1) D1 receptors are Gs receptors that increase cAMP. They control vascular smooth muscle of the kidneys and mesenteries.
2) D2 receptors use Gi proteins to decrease cAMP in the brain. If there is a shortage of dopamine in the nigrostraital tract it causes Parkinson’s disease which can be treated with D2 agonists like bromocriptine. But there are many places with D2 receptors so that causes side effects.
3) D3 , D4, D5 receptors are also located in the CNS but we don’t care except to know that D4 receptors are primarily located in the straitum and a selective D4 agonist can treat Parkinson’s without as many side effects.
1) a1 receptors function by Gq proteins to activate phospholipase C or A2 to cleave DAG and IP3. a1 receptors function to contract most sympathetic things that are stimulated by adrenergics except for the heart (b1) and adipocytes (b3). This includes some vasoconstriction (in the GI) , constriction of sphincters and so forth.
2) a2 receptors function by Gi proteins that decrease cAMP. They only function in some presynaptic terminals and in the pancreatic islet cells.
1) b1 receptors act via Gs proteins to increase cAMP and stimulate increases in all cardiac mechanisms.
2) b2 receptors act via Gs proteins to increase cAMP. It is stimulatory but carries out jobs where it shuts things off for the sympathetic system as it causes vasodilatation and relaxation of the uterus. It also stimulates aqueous humor production that needs to be inhibited in glaucoma.
3) b3 receptors act via Gs proteins to stimulate lipolysis in adipocytes.
Metyrosine blocks the conversion of tyrosine to L-DOPA.
Reserpine blocks the uptake of dopamine in to vesicles.
Amphetamines cause NE release.
Tricyclic antidepressants and cocaine inhibit NE reuptake.
All the selective drugs will be coming in ANS pharmacology.
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