Acetylcholine activity

It is clear that replacement of acetylcholine activity cannot compensate for all the changes that take place in AD. 

Agents that increase acetylcholine activity can decrease manic symptoms (e.g, use of cholinesterase inhibitors or augmentation of muscarinic cholinergic activity). 

Agents that decrease acetylcholine activity can alleviate depressive symptoms (i.e, anticholinergic agents). 

Early synthetic spasmolytics resembled atropine closely, e.g. homatropine (the ester of mandelic acid and tropine (IV)). It may be noted that acetylcholine itself is an ester of a quaternary aminoalcohol and a short-chain organic acid. If the length of the chain is increased, acetylcholine activity decreases and com-... 

Just as too much acetylcholine activity can be a problem, so can too little. Botulinum toxin is a mixture of eight proteins that act to inhibit the release of acetylcholine. This toxin is the product of the anaerobic bacterium Clostridium botulimm. Ingestion of this toxin causes the life-threatening food poisoning known as botulism. 

There are three ways to increase acetylcholine activity (1) increase the supply of acetylcholine, (2) directly stimulate acetylcholine receptors (muscarinic agonists), and (3) block the enzyme that inactivates acetylcholine (cholinesterase inhibitors). Let s take a look at each of these approaches. 

Live to acetylcholine activity. When this happens, the classic symptoms of Parkinson s disease emerge inclnding a tremor, stiffness and rigidity, a stooped posture, a masklike expressionless face, and a slow shuffling gait. 

A host of medications have been nsed to treat TD including medications that block norepinephrine activity (clonidine and propranolol), dopamine-activating medications (bromocriptine), benzodiazepines, acetylcholine-activating medications, calcium channel blockers, and monoamine oxidase inhibitors. In addition, vitamin E supplementation and atypical antipsychotics including clozapine have been used to treat TD. 

Medications that enhance acetylcholine activity are the mainstay of treatment for Alzheimer s disease and other dementias. They have found little other use in... 

TABLE 13.7. Medications that Enhance Acetylcholine Activity... 

Atropine, a tertiary amine, competitively antagonizes acetylcholine activity. Full therapeutic doses of atropine produce definite and prolonged inhibitory effects on the motor activity of the stomach, duodenum, jejunum, ileum, and colon, characterized by a decrease in tone and in amplitude and frequency of peristaltic contractions. 

Alterations in neurophysiological activity are subserved by many of the neurotransmitters discussed earlier in this section, as well as in Mechanism of Action in Chapter 7. After repeated seizures spaced over a given period of time (usually two to three times per week over a 3- to 5-week period), there is an increase in cerebral blood flow (primarily the result of increased systemic circulation) and an acute and sustained increase in cerebral metabolism. One of the most characteristic changes is a slowing in the electroencephalographic (EEG) pattern over a series of ECT treatments, associated with increased acetylcholine activity. Increases in amplitude and decreases in frequency appear to affect thalamocortical and diencephalic structures, which may modulate recently acquired behavior, such as psychosis or melancholic features. 

I disagree with Dr. Thomas that there are no known biological channels or carriers. I know of at least one example of a clearly demonstrated channel. This is the acetylcholine activated channel in denervated muscle demonstrated so elegantly by Neher and Sackmann (Nature, 260, 119, 1976), who resolved unit conductance jumps that are far too large to be accounted for by a carrier mechanism. A less unambiguously demonstrated example of channels are the Na+ and K+ channels of nerve, which both by noise analysis and pharmacological evidence imply the movement of about 1000 times as many ions in a unit of time as is reasonable for any diffusive carrier mechanism across the entire membrane. 

How can enhancement and blockade of the same system result in such dissimilar alterations in consciousness In the case of acetylcholine, we find the answer not only in spatial differentiation, but also in the fact that acetylcholine activates the cortex in both waking and REM sleep but has quite different effects on consciousness because of the other neuromodulators serotonin and norepinephrine that are (in waking) or are not (in REM sleep) co-released. 

FIGURE 11-9. Dopamine and acetylcholine have a reciprocal relationship in the nigrostriatal dopamine pathway. Dopamine neurons here make postsynaptic connections with cholinergic neurons. Normally, dopamine suppresses acetylcholine activity. 

FIGURE 11—10. This figure shows what happens to acetylcholine activity when dopamine receptors are blocked. As dopamine normally suppresses acetylcholine activity, removal of dopamine inhibition causes an increase in acetylcholine activity. Thus, if dopamine receptors are blocked, acetylcholine becomes overly active. This is associated with the production of extrapyramidal symptoms (EPS). The pharmacological mechanism of EPS therefore seems to be a relative dopamine deficiency and an acetylcholine excess. 

FIGURE 11 — 11. One compensation for the overactivity of acetylcholine that occurs when dopamine receptors are blocked is to block the acetylcholine receptors with an anticholinergic agent. Thus, anticholinergics overcome excess acetylcholine activity caused by removal of dopamine inhibition when dopamine receptors are blocked by conventional antipsychotics. This also means that extrapyramidal symptoms (EPS) are reduced. 

Kaufman R, Rogers GA, Fehlmann C, Parsons SM (1989) Fractional vesamicol receptor occupancy and acetylcholine active transport inhibition in synaptic vesicles. Mol Pharmacol 36 452 158. 

Nakatsuka T, Gu JG (2001) ATP P2X Receptor-mediated enhancement of glutamate release and evoked EPSCs in dorsal horn neurons of the rat spinal cord. J Neurosci 21 6522-31 Nakazawa K (1994) ATP-activated current and its interaction with acetylcholine-activated current in rat sympathetic neurons. J Neurosci 14 740-50 Narkiewicz K, van de Borne PJ, Hausberg M, Cooley RL, Winniford MD, Davison DE, Somers VK (1998) Cigarette smoking increases sympathetic outflow in humans. Circulation 98 528-34 Nicoll RA, Schmitz D (2005) Synaptic plasticity at hippocampal mossy fibre synapses. Nat Rev Neurosci 6 863-76... 

Baum reported a potentiometric determination of acetylcholine activity using an organic-cation-selective electrode [15], The performance of a liquid membrane electrode selective for acetylcholine (Corning No. 476.200) was investigated. Measurements of the potential difference at various concentration of acetylcholine were made against a calomel reference-electrode. 

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