Molecular mechanisms of the positive reinforcing effect of nicotine

Animal models of nicotine dependence are fundamental experimental tools for the understanding of the neurobiological and molecular processes underlying smoking behaviour. Substance use is controlled by four main processes: positive reinforcing effects, aversive effects, discriminative effects and stimulus-conditioned effects of the drug. In this article, the molecular and neural bases of the positive reinforcing effects of nicotine are summarized, focusing on data obtained in experiments including unambiguous and objective measurements of the reinforcing properties of nicotine. Operant behaviour paradigms, in particular intravenous nicotine self-administration, offer such a possibility within a solid theoretical framework. Nicotine self-administration produces changes in the mesocorticolimbic DA system, a key component of the reward system, as do other addictive drugs. The role of the mesocorticolimbic DA system as the main substrate of the reinforcing properties of nicotine is supported by converging experiments, including the evidence that nicotine self-administration is attenuated in mutant mice lacking the beta2 subunit of neural acetylcholine nicotinic receptor. The long-term adaptive molecular changes in the target neurons of the terminal fields of the mesocorticolimbic DA system, including transcriptional regulation mediated by c-fos family gene products on other genes, suggest that the mesolimbic DA projection to the nucleus accumbens is mainly involved in the stimulus-reward learning process. These data represent an initial set of information only, which may help to develop a more complete and reliable model of the molecular dynamics underlying the reinforcing effects of nicotine.