NICOTINIC ACETYLCHOLINE RECEPTORS

Nicotinic Acetylcholine Receptors

Nicotinic Acetylcholine Receptors

Q1. Nicotine Interaction with the Cholinergic Transmission System

A wealth of data shows that drugs such as scopolamine can induce impairments in learning and memory and that procholinergic drugs, especially acetylcholinesterase inhibitors, can ameliorate such impairments (Fibiger 1991, Mohammed 1993). More recent experiments focus on specific acetylcholine receptor subtypes in mediating the effects of acetylcholine on cognition. There is an emerging consensus that blockade of the muscarinic M1 subtype of acetylcholine receptor is particularly associated with memory impairment (Bymaster et al 1993) and that M2 receptor antagonists may be associated with improvements in memory, including attenuating the effects of M1 receptor blockade, perhaps by increasing acetylcholine release.

Nicotinic receptor antagonists do not appear to impair cognitive function in the same way as antimuscarinic drugs, but nicotine itself has been shown to improve aspects of cognitive performance, such as attentional function, in human beings, including those with early stage Alzheimer's disease. Nicotine has also been shown to enhance short-term memory in a delayed matching-to-sample task in monkeys, an effect that was reversed by treatment with scopolamine (Terry et al 1993).

Nicotine Antagonists Block the 'Satisfaction' Levels of Smoking

A great deal of evidence supports the view that people continue to smoke tobacco products, despite the widely publicized health risks associated with smoking, because of the reinforcing effects of nicotine. Substantial research literature suggests that nicotine contributes to and interacts with cigarette smoking behavior. It appears to be primarily the central actions of nicotine that tobacco smokers seek, and animal studies confirm the importance of central nicotinic actions in controlling behavior.

Nicotine blockade therapy represents an alternative pharmacotherapeutic approach to tobacco use and cigarette smoking cessation. Nicotine blockade therapy is radically different from other approaches, since it should permit "pharmacological extinction" of smoking behavior. Smokers attempting to quit by this method would be administered a centrally-active nicotinic receptor antagonist while continuing to smoke. With every puff, the association between smoking and delivery of nicotine-associated reinforcement would be unlearned. This should reduce long-term craving and hence provide much lower relapse rates than other approaches.

Neuromodulatory Effects of Acetylcholine

New ways of enhancing brain cholinergic function are also in development. For example, ß-carboline inverse agonists at the benzodiazepine receptor can disinhibit cholinergic neuronal activity in the basal forebrain by opposing the inhibitory effects of GABA at receptors on these neurons, thereby increasing acetylcholine release in the neocortex (Sarter et al 1988). More recently, antagonists at the galanin receptor have been reported to enhance both acetylcholine release and spatial learning in rats, though there are reports to the contrary. The approach follows from the demonstration of the coexistence of the neuropeptide galanin in some forebrain cholinergic neurons, especially in the medial septum. Molecular biology has also influenced this research. For example, fibroblasts have been genetically modified to express the acetylcholine biosynthetic enzyme, choline acetyltransferase (ChAT), to produce and release acetylcholine when implanted into the brain (Fisher et al 1991). Such transplanted cells can apparently restore cognitive functions in rats with forebrain ...