ABSTRACT
Nicotine has a wide variety of effects on brain and body functions. Insights into the bases for these effects at systems, organ, cellular, and molecular levels have been accumulating; however, neurochemical and behavioral endpoints that remain evident or emerge after chronic dosing are likely to be most relevant to nicotine dependence. A better understanding at the molecular level is needed with regard to how chronic nicotine exposure affects the balance between functional activation and inactivation of nicotinic acetylcholine receptors (nAChRs). Also warranting attention are effects beyond ion channel function and involving adaptation to nicotine exposure of the nervous system and nAChR expression. Further complicating these issues is the diversity in nAChR subtypes, each of which is distinguished and defined by its subunit composition, unique pharmacological profile, and characteristic sensitivity to acute or chronic nicotine. Successful development of medications for smoking cessation, or to mimic effects of nicotine that may prove beneficial in the treatment
of neurological and psychiatric disorders, will require a better understanding of both the short-and long-term effects of nicotine and the nAChR subtypes that dominate the neurochemical and behavioral effects of interest. The biggest challenges will be to define how the effects of nicotine are integrated across nAChR subtypes (processes that may change through adaptive mechanisms) to determine whether agonism, antagonism, partial agonism, and allosteric modification are features that should be sought and to ascertain whether the highest ratio of beneficial to adverse effects of the actions of nicotine is better achieved by targeting downstream responses alone or in some combination with a specific nAChR subtype.
