Alcohol administration is known to inhibit the secretion of the hypothalamic-neurohypophysial peptide, oxytocin. Recent studies suggest that this neuropeptide may be important in the development of tolerance to alcohol and other drugs. Thus, in alcoholism, a self-perpetuating cycle could develop in which alcohol inhibits oxytocin secretion which in turn allows for tolerance to be established. The objective of this proposal is to investigate the relation between alcohol intake and the central oxytocin axis. The focus will be on the study of the changes in OT mRNA and peptide levels in specific hypothalamic and extrahypothalamic regions in response to acute and chronic alcohol consumption in male and female rats. Oxytocin is synthesized in specific hypothalamic nuclei that project to several different areas of the brain. The supraoptic nucleus (SON) sends oxytocin projections primarily to the posterior pituitary while the paraventricular nucleus (PVN) innervates the pituitary as well as brain areas involved in memory, emotion, motivation and autonomic reflexes. There are other accessory hypothalamic nuclei that synthesize only oxytocin however, the axon destination of these neurons is not entirely understood. Thus, the anatomical specificity of this system makes it an ideal neuronal system to study. The hypothesis to be tested is that alcohol decreases steady-state oxytocin mRNA levels as well as secretion of the peptide in specific brain areas associated with cognition and behavior. These areas include: the olfactory and limbic areas, the brainstem and spinal cord. Oxytocin mRNA and peptide levels will be measured in microdissected nuclear areas and central projection areas. Experiments are designed to: 1) determine the effect of acute and chronic alcohol consumption on oxytocin mRNA levels in the hypothalamic nuclei, and levels of this peptide in specific extrahypothalamic areas (spinal cord, brain stem and limbic areas) in female and male adult rats; 2) evaluate the effect of chronic alcohol on the responsiveness of the oxytocin system under physiological conditions in which its secretion is stimulated; 3) evaluate the involvement of central gama-aminobutyric acid (GABA) neurons in the interactions between alcohol and the central oxytocin axis in alcohol exposed animals; and 4) To examine the hypothesis that, in the female, gonadal steroids alter the effect of alcohol on OT pathways via a GABA receptor. These experiments will utilize ovariectomized female rats and steroid replacement to examine the efficacy of alcohol and GABA mimetics on OT mRNA and extrahypothalamic OT levels. These studies will elucidate basic neuroendocrine mechanisms that are involved in the disease of alcoholism which hopefully will lead to the development of new methods for its treatment.