A biochemical model of nicotine dependence

ORTELLS, MARCELO OSCAR; BARRANTES, GEORGINA ELIDA

Montreal

Congreso; World Congress on Brain, Behavior and Emotions; 2014

Introduction 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 nicotinic receptor 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. Objectives We analyzed 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. Results and Conclusions We propose that negative feedbacks on dopamine release regulated by a4b2 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. Nicotine addiction is established because this alkaloid first abolishes transitorily a mechanism that inhibits brain reward processes, but it enhances their actions after long-term use. These processes can be at the neuronal and/or molecular levels. The vicious circle starts when the smoker tries to ?solve? the problem of the enhanced rewarding inhibitory system (an unpleasant feeling when the smoker is not smoking), by using the same drug that started it. The smoker gets a temporarily relieve, but worsening the addictive condition in the long term. We conclude that pharmacological therapies based on nicotine itself would not be possible, at least without the help of behavioral treatment. Pharmacological therapies should be based ideally on drugs that specifically inhibit, at least partially, the a4b2 nAChR without inducing its upregulation.