The purpose of this application is to study correlated responses to selection in lines of mice which have been selectively bred to differ in their responses to nicotine. Animals selectively bred for a drug-related trait provide clear evidence of a heritable component for that trait. The mice to be used in this study are currently being produced in another NIDA-sponsored project. Animals are tested for sensitivity to nicotine using locomotor activity in a Y-maze over 3 minutes following administration of a low dose of nicotine (0.75 mg/kg). A residual score (difference in observed and expected drug activity) is calculated from regression of drug score on saline score for each animal. The most severely affected mice (greatest negative residual; low activity following nicotine) are mated to form the Nicotine-Depressed lines, the least affected mice (greatest positive residual; high activity following nicotine) are mated to form the Nicotine-Activated lines. A random sampling of individuals are mated at random to form the Control lines, Duplicate Nicotine Depressed, Nicotine activated, and Control lines are being produced. For this application we propose to measure parameters thought to be involved in mediating actions of nicotine as potential correlated responses to selection. For these nicotine-selected lines, we will measure brain nicotine receptors and corticosterone responses in vivo and in vitro. Pharmacokinetics of nicotine will be measured to determine if differences in drug metabolism occur as correlated responses to selection. These studies should allow us to determine if traits known to influence responses to nicotine change in the predicted direction during selection for differential sensitivity to nicotine. Correlations between behavioral and biochemical measurements may be used to determine if the two traits are mediated by common mechanisms.