Edinger-Westphal Urocortin-1 Involvement in Binge Ethanol Intake and Reward

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Stress plays a key role in precipitating relapse to excessive ethanol (EtOH) consumption in dependent alcoholics. Even in non-dependent populations, evidence supports a role for neural stress networks, such as the corticotropin-releasing factor (CRF) system, in excessive EtOH intake. Unfortunately, the complex neuroanatomical and pharmacological features of the CRF system have hindered our understanding of the roles of its specific components in EtOH-related behaviors. To this end, we have devoted years of study to the examination of Urocortin-1 (Ucn1), an endogenous ligand of the CRF system that is closely related to the prototypical ligand CRF, yet binds to both CRF receptors with higher affinity than CRF itself. While the fields of alcohol abuse and addiction have typically focused on the mesolimbic dopamine pathway and brain structures such as the ventral tegmental area and nucleus accumbens, our laboratory has provided converging lines of evidence to support a role for the centrally-projecting neurons of the Edinger-Westphal nucleus (EWcp) in EtOH intake and sensitivity. The primary site of Ucn1 expression in the brain is within the EWcp, and a relationship between EWcp-Ucn1 expression and a genetic predisposition to excessive EtOH intake has been identified. Further interest in the EWcp as a brain region involved in EtOH intake is based on the observation that in addition to Ucn1, the cocaine- and amphetamine-regulated transcript (CART) neuropeptide, and the ghrelin receptor (Ghsr) are both highly expressed within EWcp. Intriguingly, these proteins have also been implicated in excessive EtOH consumption and EtOH-induced reward, and we have hypothesized that the role of the EWcp in excessive EtOH consumption is dependent on the interactions between Ucn1 and CART, Ghsr, and additional proteins. Thus, Specific Aim 1 of this proposal seeks to use quantitative PCR array technology elucidate interactions between Ucn1 and other EWcp-enriched genes that are relevant for EtOH-related behaviors, and Specific Aim 2 of my proposal seeks to examine well-characterized behavioral models of EtOH binge-drinking and EtOH- induced reward following knockdown of Ucn1 expression within the EWcp, using lentiviral-mediated RNA interference. These highly innovative experiments will not only conclusively determine the importance of EWcp-Ucn1 in two relevant behavioral endophenotypes of alcoholism, but will also use quantitative gene expression analyses to aid in unraveling the complex role that the EWcp plays in excessive EtOH intake.