Many people drink, but only some become alcoholic. Genetic factors likely play a role, but environmental factors such as stress may also be involved. Because of the possibility to manipulate both genetic and environmental factors, mice are the species of choice for the experimental study of gene-environment interactions. Alcohol and drug abuse are likely related to subjective effects, and such effects in humans can often be predicted from drug discrimination experiments in animals. Learning to discriminate a drug from its vehicle generally takes animals several months. Recently, a novel procedure was introduced in which mice acquire a drug discrimination in less than two weeks. The present application is aimed at exploiting this potentially useful drug discrimination methodology to examine genetic determinants of sensitivity to alcohol. Studies under Specific Aim I examine the sensitivity of different mouse strains to the discriminative stimulus effects of alcohol, and test the hypothesis that DBA/2J mice are more sensitive than C57BL/6J mice to these effects. For each of the strains, different groups of mice will be trained to discriminate alcohol at different doses, and training dose / discrimination accuracy data will be used to compare the sensitivity of the different strains. Studies under Specific Aim II begin to identify genetic factors that contribute to differences in the discriminative stimulus effects of alcohol, and test the hypothesis that mice with reduced or no expression of the serotonin transporter are less sensitive to the discriminative stimulus effects of alcohol. The approach will 1) exploit a procedure for rapidly assessing abuse-related effects of alcohol in mice, 2) provide new information about genetic determinants of sensitivity to alcohol, and 3) provide a comparative basis for future studies of developmental aspects of alcohol and drug abuse. Initiation of drug abuse occurs primarily during adolescence, and during this developmental period, drugs of abuse may have distinct effects, which could increase risk for abuse. In rodents, adolescence has been defined as spanning from postnatal days 28-42. Being able to train a discrimination within this two-week period is a prerequisite for studying the discriminative stimulus effects of drugs during adolescence in a rodent model. Thus, the rapid drug discrimination procedure in mice may be especially suitable to examine developmental aspects of abuse related drug effects. This future research will increase our understanding of risk factors for alcoholism and drug abuse and will help the development of effective approaches to prevention and treatment. ? ? ?
