Acetylcholine enhancement

Hikida, T., Kitabatake, Y., Pastan, I., Nakanishi, S. Acetylcholine enhancement in the nucleus accumbens prevents addictive behaviors of cocaine and morphine. Proc. Natl. Acad. Sci. U.S.A. 100 6169, 2003. 

The key to managing the side effects of acetylcholine-enhancing medications is first and foremost using medications that are more easily tolerated. Second, these medications should be started at low doses and slowly increased over a period of several weeks. 

Effects Pleasant drowsiness, skeletal muscle relaxation, slowing of heartbeat, dilation of coronary vessels, inhibition of acetylcholine, enhancement of epinephrine, slight reduction of blood pressure, cooling of body, mild intoxication and giddiness, darkening of vision, auditory hallucinations (sounds seem distant), and increased memory function. 

Several cholinergic strategies, other than cholinesterase inhibition, have been employed with the intention of ameliora ting the symptoms of AD. These include precursor loading acetylcholine release enhancement, and direct activation of both muscarinic and nicotinic receptors. 

An alternative approach to stimulate cholinergic function is to enhance the release of acetylcholine (ACh). Compounds such as the aminopyridines increase the release of neurotransmitters (148). The mechanism by which these compounds modulate the release of acetylcholine is likely the blockade of potassium channels. However, these agents increase both basal (release in the absence of a stimulus) and stimulus-evoked release (148). 4-Aminopyridine [504-24-5] was evaluated in a pilot study for its effects in AD and found to be mildly effective (149). 

Compounds that affect activities of hepatic microsomal enzymes can antagonize the effects of methyl parathion, presumably by decreasing metabolism of methyl parathion to methyl paraoxon or enhancing degradation to relatively nontoxic metabolites. For example, pretreatment with phenobarbital protected rats from methyl parathion s cholinergic effects (Murphy 1980) and reduced inhibition of acetylcholinesterase activity in the rat brain (Tvede et al. 1989). Phenobarbital pretreatment prevented lethality from methyl parathion in mice compared to saline-pretreated controls (Sultatos 1987). Pretreatment of rats with two other pesticides, chlordecone or mirex, also reduced inhibition of brain acetylcholinesterase activity in rats dosed with methyl parathion (2.5 mg/kg intraperitoneally), while pretreatment with the herbicide linuron decreased acetylcholine brain levels below those found with methyl parathion treatment alone (Tvede et al. 1989). 

Acetylcholine-mediated parasympathetic activity leads to production of the non-adrenergic-non-cholinergic transmitter nitric oxide. By enhancing the activity of guanylate cyclase, nitric... 

Birdsall NJ, Farries T, Gharagozloo P, Kobayashi S, Kuonen D, Lazareno S, Popham A, Sugimoto M. Selective allosteric enhancement of the binding and actions of acetylcholine at muscarinic receptor subtypes. Life Sci 1997 60 1047-1052. 

Parasympathetic stimulation causes a decrease in heart rate. Acetylcholine, which stimulates muscarinic receptors, increases the permeability to potassium. Enhanced K+ ion efflux has a twofold effect. First, the cells become hyperpolarized and therefore the membrane potential is farther away from threshold. Second, the rate of pacemaker depolarization is decreased because the outward movement of K+ ions opposes the effect of the inward movement of Na+ and Ca++ ions. The result of these two effects of potassium efflux is that it takes longer for the SA node to reach threshold and generate an action potential. If the heart beat is generated more slowly, then fewer beats per minute are elicited. 

Bernard, R., Lydic, R. Baghdoyan, H. A. (2006). Hypocretin (orexin) receptor subtypes differentially enhance acetylcholine release and activate G protein subtypes in rat pontine reticular formation./. Pharmacol. Exp. Ther. 317, 163-71. 

Kodama, T., Takahashi, Y. Honda, Y. (1990). Enhancement of acetylcholine release during paradoxical sleep in the dorsal tegmental field of the cat brain stem. Neurosci. Lett. 114, 277-82. 

Lydic, R., Baghdoyan, H. A. Lorinc, Z. (1991). Microdialysis of cat pons reveals enhanced acetylcholine release during state-dependent respiratory depression. Am. J. Physiol. 261, R766-70. 

Intracerebroventricular infusion of CST-14 dramatically increases the amount of slow wave activity in rats, at the expense of wakefulness. The mechanism by which CST-14 enhances cortical synchronization has been established through the interaction of CST-14 with acetylcholine, a neurotransmitter known to be involved in the maintenance of cortical desynchronization. Application of acetylcholine (ACh) in the anesthetized animal increases fast activity, and this effect is blocked with the simultaneous addition of CST-14. These data suggest that CST-14 increases slow wave sleep by antagonizing the effects of ACh on cortical excitability. In addition to this mechanism, cortistatin may enhance cortical... 

---