Acetylcholine action mechanism

Leopold and Comroe2 studied the use of 0 05, 01 and 0-2 per cent D.F.P. in arachis oil in glaucoma, and found that cases unrelieved by eserine responded readily to 01 per cent D.F.P. instilled into the conjunctival sac. However, the action of D.F.P. in the glaucomatous eye lasts for about 12 hr. compared to an action of about 12 days in the normal eye. The short-lived action of D.F.P. in cases of raised intra-ocular tension lends evidence to the suggestion that there may be an upset of the acetylcholine-cholinesterase mechanism in glaucoma. There are certain side effects such as ciliary spasm and headache which may prove troublesome during treatment. 

Fig. 1 Mechanism of acetylcholine action. Formed in the synapse, the compound is released by exocytosis into the synaptic cleft, where it is rapidly hydrolyzed by acetylcholinesterase...

In the case of mercury-induced diuresis interference with ATPase and subsequent imbalance of the Na/K transport system may be involved. The large cations may also affect ATPases, in this case that responsible for Ca transport. The calcium blocking could increase the release of neurotransmitters such as acetylcholine. The mechanism of action of nitroprusside may involve a chain of events eventually leading to a lowering of calcium ion concentration and muscle contraction. 

Mode of Action. All of the insecticidal carbamates are cholinergic, and poisoned insects and mammals exhibit violent convulsions and other neuromuscular disturbances. The insecticides are strong carbamylating inhibitors of acetylcholinesterase and may also have a direct action on the acetylcholine receptors because of their pronounced stmctural resemblance to acetylcholine. The overall mechanism for carbamate interaction with acetylcholinesterase is analogous to the normal three-step hydrolysis of acetylcholine however, is much slower than with the acetylated enzyme. 

In order to understand the exact mechanism of the neurotoxic action, it is important to know the secondary structure of the neurotoxins as well. It is now known that postsynaptic neurotoxins attach to the a-subunits of acetylcholine receptor (AChR). 

To achieve their different effects NTs are not only released from different neurons to act on different receptors but their biochemistry is different. While the mechanism of their release may be similar (Chapter 4) their turnover varies. Most NTs are synthesised from precursors in the axon terminals, stored in vesicles and released by arriving action potentials. Some are subsequently broken down extracellularly, e.g. acetylcholine by cholinesterase, but many, like the amino acids, are taken back into the nerve where they are incorporated into biochemical pathways that may modify their structure initially but ultimately ensure a maintained NT level. Such processes are ideally suited to the fast transmission effected by the amino acids and acetylcholine in some cases (nicotinic), and complements the anatomical features of their neurons and the recepter mechanisms they activate. Further, to ensure the maintenance of function in vital pathways, glutamate and GABA are stored in very high concentrations (10 pmol/mg) just as ACh is at the neuromuscular junction. 

McCormick, DA and Prince, DA (1986a) Mechanism of action of acetylcholine in the guinea-pig cerebral cortex in vitro. J. Physiol. 375 169-194... 

Neonicotinoids are potent broad-spectrum insecticides that exhibit contact, stomach and systemic activity. Acetamiprid, imidacloprid, nitenpyram, thiamethoxam and thiacloprid are representatives of the neonicotinoid insecticides (Figure 1). The mechanism of action is similar to that of nicotine, acting on the central nervous system causing irreversible blocking of postsynaptic nicotinic acetylcholine receptors (nAChR). Neonicotinoid insecticides are often categorized as antagonists of the... 

Many measurements in pharmacology rely on a chain of events following receptor activation to produce a measurable response — for example, contraction of the smooth muscle of a piece of guinea-pig ileum in response to muscarinic receptor activation by acetylcholine. This means that the relationship between receptor occupancy and response is likely to be complex, and mechanisms of drug action in such systems are often difficult to define. 

The answer is a. (Katzung, p 482.) Phenothiazines as a class and, in particular, the aliphatic phenothiazines are most likely to produce marked sedation. The mechanism of action for this effect is associated with its ability to block histamine and acetylcholine receptors. 

There is evidence for the contribution of serotonin dysfunction to mania, and in the mechanism of action of mood stabilizers [19], however, specific data on the serotonergic system and mania are fewer and variable. Moreover, altered functioning of other neurotransmitters in mania such as norepinephrine, dopamine, acetylcholine, and GABA, and their interaction with serotonin, are also likely to be involved in the pathogenesis of mood disorders. Differences in these neurotransmitter systems possibly underlie differences in the pathogenesis of depressive and manic episodes. 

Hopf2 concludes that although insect nerve tissues produce substances that simulate acetylcholine and a cholinesterase which is inhibited by organo-phosphorus insecticides, these substances (in locusts at any rate) are not antagonized by atropine. Furthermore, tubocurarine does not poison insects, although it is active in warm-blooded animals and affects the neuromuscular junctions (see pp. 36, 37). In short, different physiological mechanisms appear to be at work in insects. In particular, it seems that acetylcholine, when injected into a variety of insects, has no marked toxic action. It seems then that, in some... 

Although some steroids have been reported to reduce the toxic effects of some insecticides, the steroid ethylestrenol decreased the rate of recovery of depressed cholinesterase activity in disulfoton- pretreated rats (Robinson et al. 1978). The exact mechanism of this interaction was not determined. Ethylestrenol alone caused a small decrease in cholinesterase activity, and, therefore, resulted in an additive effect. Rats excreted less adrenaline and more noradrenaline when given simultaneous treatments of atropine and disulfoton compared with rats given disulfoton alone (Brzezinski 1973). The mechanism of action of disulfoton on catecholamine levels may depend on acetylcholine accumulation. In the presence of atropine, the acetylcholine effect on these receptors increases the ability of atropine to liberate catecholamines. 

Traditionally, most affective disorders have been treated with compounds that resemble the neurotransmitters that are deficient or in excess in specific brain regions. The aberrant levels of neurotransmitters (or their receptors), such as norepinephrine, dopamine, acetylcholine, and serotonin, have correlated with behavioral symptoms of schizophrenia, depression, anxiety, sleep disorders, motor dysfunctions, attention difficulties, and cognitive disorders. Most drugs discovered for these disorders resulted from screening compounds directly in rodent behavioral models that mimic the behavior of the disease. In these cases, the molecular target" or mechanism of action was assumed to be the deficiency or excess of a neurotransmitter. 

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