Neurochemical mechanisms underlying

ORTELLS, MARCELO OSCAR; ARIAS, H.

Pharmacology of Nicotinic Acetylcholine Receptors from the Basic and Therapeutic Perspectives

Research Signpost

Lugar: Kerala; Año: 2011; p. 199 - 221

Tobacco smoking remains a global major health issue. It is known that the alkaloid nicotine is the main psychoactive substance present in tobacco, targeting neuronal nicotinic acetylcholine receptors (AChRs). However, a full understanding of the mechanisms by which this drug establishes and maintains smoking addiction is lacking. The main effects of nicotine associated with smoking are AChR activation, desensitization, and upregulation, with the subsequent modulation of the mesocorticolimbic dopaminergic and habenulointerpeduncular cholinergic systems. However it is far from clear how nicotine dependence might be established on those grounds. Receptor upregulation is an unusual effect for a drug of abuse because it is expected that a chronic exposure down-regulates receptor numbers. Receptor upregulation and receptor desensitization are commonly viewed as opposite, homeostatic mechanisms. We here evaluate the available information on smoking addiction, and drugs employed as aids in smoking cessation. We especially focus on a recent model of nicotine dependence in which both receptor upregulation and receptor desensitization are responsible for establishing a biochemical mechanism of nicotine dependence. A conclusion of this model is that drugs used for smoking cessation should inhibit preferentially á4â2-containing AChRs and to have a low or null ability to upregulate AChRs, as this characteristic should allow smokers to achieve down-regulation without abstinence symptoms.