Use of knock-out mice to determine the molecular basis for the actions of nicotine.

Recombinant DNA techniques have been used to identify the family of molecules that mediate nicotine's effects on the brain. Nicotine binds and activates nicotinic acetylcholine receptors (nAChRs) which are made up of combinations of individual nicotinic subunits. It is important to determine which of the many possible subunit combinations are responsible for the physiological and behavioral effects of nicotine that lead to addiction. Molecular genetic tools such as antisense strategies have been useful in elucidating the electrophysiological properties of nAChRs in different tissues. Use of knock-out mice lacking individual nAChR subunits has also begun to elucidate how nicotine exerts its actions from the molecular level to the behavioral level. Experiments using mice lacking the beta2 subunit of the nAChR have shown that binding of nicotine to receptors containing this subunit is the first step in a pathway leading to increased dopamine levels in the mesolimbic dopamine system, and ultimately to the behavioral effects of nicotine in a test of nicotine reinforcement. Mice deficient in various alpha subunits of the nAChR will identify the partners of beta2 mediating the addictive properties of nicotine. In addition, more data needs to be gathered on the electrophysiological properties of different subunit combinations, the effects of nicotine on different neurotransmitter systems and the links between the molecular biology of nicotine receptors, their physiology and the ultimate role of individual receptor subtypes in complex behaviors. Multidisciplinary approaches to nAChR function will be essential to answering these questions.