NEUROBEHAVIORAL MECHANISMS OF NICOTINE ACTION - ROLE IN THE INITIATION AND MAINTENANCE OF TOBACCO DEPENDENCE

Basic neuroscience research conducted over the last quarter century ha s provided us with much information concerning potential biobehavioral and neuromolecular mechanisms involved in the initiation and maintena nce of tobacco dependence. Nicotinic-acetylcholinergic receptors (AChR s), in addition to having a primary locus on cholinergic neurons, appe ar to be also located on a variety of noncholinergic neurons (presynap tic and/or postsynaptic sites). Nicotine therefore appears to be able to affect a variety of neuronal pathways involved in behavioral reward and arousal processes, which appear paramount to tobacco dependence. Nicotine appears to have several unique properties at the cellular lev el that allow it to act both as an agonist and as a potential antagoni st at select AChRs. Nicotine's ability to act as an agonist appears to be contingent on an action at nAChRs, which initially open a receptor -linked cation channel, eliciting the entrance of CA++ (or other catio ns) into the cell. Cation entrance into the cell, therefore, may be th e cellular transducer of nicotine's behavioral and dependence-producin g effects. Subsequent to this initial agonist effect, the nicotinic re ceptor is believed to undergo a refractory period, via a desensitizati on process, during which Ca++ is prevented from further entrance into the cell. It is this ability to induce receptor desensitization which seems central to nicotine's ability to act as an antagonist. The durat ion of nAChR desensitization may also be useful in explaining individu al variability to nicotine's behavioral effects and may be related to the induction of acute and/or chronic tolerance in both animals and ma n. Nicotine-induced desensitization may also be important to relapse i n the smoker if conditioned stimuli are able to provoke such mechanism s, which could lead to the need to smoke. Finally, a model is presente d to account for individual smoking patterns and level of tobacco depe ndence which is partially based on the proposed cellular mechanisms of nicotine action and desensitization at the nAChR.