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 underlyin g smoking behaviour. Substance use is controlled by four main processes: po sitive reinforcing effects, aversive effects, discriminative effects and st imulus-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 object ive measurements of the: reinforcing properties of nicotine. Operant behavi our paradigms, in particular intravenous nicotine self-administration, offe r such a possibility within a solid theoretical framework Nicotine self-adm inistration produces changes in the mesocorticolimbic DA system, a key comp onent of the reward system, as do other addictive drugs. The role of the me socorticolimbic DA system as the main substrate of the reinforcing properti es of nicotine is supported by converging experiments, including the eviden ce that nicotine self-administration is attenuated in mutant mice lacking t he beta 2 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 medi ated by c-fos family gene products on other genes, suggest that the mesolim bic DA projection to the nucleus accumbens is mainly involved in the stimul us-reward learning process. These data represent an initial set of informat ion only, which may help to develop a more complete and reliable model of t he molecular dynamics underlying the reinforcing effects of nicotine. (C) 1 999 Lippincott Williams & Wilkins.