Recent data have shown that central oxytocin pathways constitute an important component of the inhibitory controls of ingestion of both food and salt (NaCl) in rats. Since central oxytocin-mediated inhibition of ingestion appears to be generalized to many different solutes, we postulate that similar central control mechanisms may also influence the ingestion of ethanol. The studies proposed in this application will directly address this hypothesis by assessing the effects of reversible antagonism of oxytocin receptors and irreversible destruction of central oxytocin-receptor bearing cells on the consumption of ethanol by laboratory rats. Preliminary studies utilizing central administration of the toxic A chain of the plant cytotoxin ricin conjugated to oxytocin have indicated that this treatment leads to a robust consumption of ethanol in rats, which then continues and leads to the development of tolerance to acutely administered ethanol. Analogous effects were reproduced by central administration of the reversible oxytocin-receptor antagonist L366,946, confirming that these are specific oxytocin effects. To fully understand the participation of central oxytocin pathways on ethanol ingestion it will first be necessary to assess the effects of ethanol to modulate central oxytocin pathways that inhibit the consumption of ordinary ingesta, such as food and NaCl solutions. Initial studies will be done to evaluate the effect of acute ethanol administration on basal, inhibited, and stimulated ingestive behavior in rats, and will correlate these effects with measured changes in central and peripheral oxytocin release. Additional studies will extend these observations to a direct assessment of the effect of exogenous administration of oxytocin on ethanol-induced modulation of ingestive behavior. These experiments will provide the basis for a comprehensive characterization of the neural mechanisms responsible for oxytocin antagonist and ricin-oxytocin potentiation of ethanol consumption in rats. The models we characterize will then be employed to study potential developmental and gender- related variables that influence ethanol consumption. The combined studies in this proposal will therefore address several important unanswered questions about central mechanisms that influence the initiation and continued consumption of alcohol in laboratory animals. They will also likely have important implications for future studies of the brain pathophysiology and adaptive neuronal mechanisms that accompany the behavioral and functional consequences of chronic alcohol abuse, which cannot be as easily evaluated in human subjects.
