Substantial evidence points to a close association between alcohol and cigarette use. A sequence of laboratory challenge studies is aimed at the general hypothesis that cigarette smoking may be causally involved in excessive drinking by decreasing the acute sensitivity to the intoxicating effects of alcohol, thereby promoted increased consumption and risk of addiction. This general hypothesis is consistent with strong evidence from animal studies of cross-tolerance between the two drugs, and with findings from a reanalysis by our group of alcohol challenge data in a Australian twin sample showing that an acute dose of alcohol produced less intoxication in smokers than in non-smokers. Measurement domains will be the same as those shown effective in prior studies, with principal emphasis on measures of balance using advanced dynamic posturography procedures (and complementary oculomotor tests). In addition subjective measures of drug effects will be obtained. Cardiorespiratory responses will be measured because of their sensitivity to nicotine as well as alcohol. The hypothesized cross- tolerance will be investigated in three studies of male and female social drinkers, ages 21 through 25. Experiment 1 will be a study of 4- hour deprived smokers in which controlled cigarette smoking will be combined with acute alcohol challenges, for comparison with conditions in which the substances are given individually or neither is administered. In an additional session, the effects of nicotine administered by nasal spray (NNS) will be assessed for comparison with smoking. It is hypothesized, consistent with prior animal and neuropharmacological evidence, that nicotine spray will produce effects similar to those seen with smoking on the critical posturographic and oculomotor measures. Experiment 2 will be similar to Experiment 1, except that nicotine spray will be given to no-smokers to allow acute effects to be identified. Experiment 3 will investigate moderate drinking MZ and same-sex DZ twin pairs discordant for nicotine dependence, to provide a direct and controlled test of the hypothesis that undeprived chronic smokers are intensely affected by a challenge dose of alcohol. Twins will be studied in two sessions, one with alcohol plus placebo NNS, and a second with alcohol plus NNS. A second aim from this study is to test for a possible genetic component to the cross tolerance, in the form of smaller intra-pair differences in MZ than in DZ twins. The findings from these experiments will provide critical evidence regarding a potential important contributor to excessive drinking.