Med Hypotheses. 2009 Dec 2. [Epub ahead of print]
Nicotine is the main psychoactive substance present in tobacco, targeting in the CNS the nicotinic acetylcholine receptors (nAChR). The main effects of nicotine associated with smoking are nAChR upregulation, nAChR desensitization and modulation of the 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 analyze the available information under a model in which both receptor upregulation and receptor desensitization are responsible for establishing a mechanism of nicotine dependence, consequently having an important role in starting and maintaining tobacco addiction. We propose that negative feedbacks on dopamine release regulated by alpha4beta2 nAChRs are disrupted by nicotine. nAChR desensitization is the disrupting mechanism, while nAChR upregulation is the reinforcing process of nicotine dependence, which eventually initiates tobacco addiction. A conclusion of the model is that drugs used for smoking cessation should inhibit preferentially alpha4beta2 nAChRs and to have a low or null ability to upregulate nAChRs, as this characteristic allows the smoker to achieve downregulation without abstinence symptoms. A relationship between this hypothesis and smoking and schizophrenia is also discussed.