Affiliations: Facultad de Medicina, Universidad de Morón –
Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET),
Morón, Argentina | Department of Pharmaceutical Sciences, College of
Pharmacy, Midwestern University, Glendale, AZ, USA
Note: [] Correspondence: Marcelo O. Ortells, Facultad de Medicina,
Universidad de Morón, Machado 914, 4° piso, 1708 Morón,
Argentina. Tel.: +54 11 4502 9460; Fax: +54 11 4502 9460; E-mail: [email protected]
Abstract: Nicotine is the main psychoactive substance present in tobacco,
targeting neuronal nicotinic acetylcholine receptors (AChRs). The main effects
of nicotine associated with smoking are AChR activation, desensitization, and
upregulation, with the subsequent modulation of the mesocorticolimbic
dopaminergic system. However, there is a lack of a comprehensive explanation of
their roles that effectively makes clear how nicotine dependence might be
established on those grounds. Receptor upregulation is an unusual effect for a
drug of abuse, because theoretically this implies less need for drug
consumption. Receptor upregulation and receptor desensitization are commonly
viewed as opposite, homeostatic mechanisms. We here review the available
information on smoking addiction, and drugs employed as aids in smoking
cessation, especially under a recently presented model of nicotine dependence.
In this model both receptor upregulation and receptor desensitization are
responsible for establishing a biochemical mechanism of nicotine dependence,
which have an important role in starting and maintaining tobacco addiction.
Basically, a conclusion of this model is that those drugs used for smoking
cessation should inhibit preferentially α4β2-containing AChRs and to have a low or
null ability to upregulate AChRs, as this characteristic allows the smoker to
achieve downregulation without abstinence symptoms.
