Opioid peptides contribute to the effects of ethanol and play a role in the development of alcoholism. For example, human populations with a genetic propensity toward alcohol abuse and dependence are reported to differ with respect to ethanol- stimulated release of b-endorphin, and these differences may affect the pharmacological properties of alcohol to contribute toward the disease state. The experiments in this proposal utilize an animal model to investigate the relationship between b-endorphin and alcohol sensitivity. We've found that genetically engineered mice that lack the ability to synthesize the peptide b-endorphin differ markedly in several measures of alcohol sensitivity, including ethanol-mediated reward, aversion and neural adaptation. Mirroring epidemiological findings from alcoholic populations, the effects of b-endorphin on alcohol response often appears to be sex- dependent. Moreover, we have found that gonadal hormones such as testosterone regulate the effect of b-endorphin on alcohol sensitivity. Despite the clear evidence linking alcohol response and b-endorphin, to date, studies reported in the literature have been correlational. In order to elucidate the mechanisms underlying this differential sensitivity we plan a series of comprehensive behavioral studies in mice with varying levels of b-endorphin. These will systematically vary ethanol exposure, b-endorphin level and sex/hormone status. In addition, neurochemical assays will be used to begin uncovering the neural consequences of low or absent b-endorphin that result in modified alcohol sensitivity. Finally, the effect of gonadal steroid hormones in modulating the ethanol's action on brain substrates will be explored. It is hoped that these studies will lead to a greater understanding of the relationship between b-endorphin and alcohol and thereby contribute to our knowledge of the mechanisms underlying human alcohol dependence. Although alcoholism and its consequences have devastating implications throughout the world and on virtually all aspects of human society, the causes are still largely unknown. The opioid peptide system is thought to be one important biological factor contributing to a liability for developing alcoholism and we use an animal model to better understand the mechanisms by which opioids modulate this risk. [unreadable] [unreadable] [unreadable]