GRANT NUMBER: R01 DA006214-25S1  

ABSTRACT:   In this supplement application, we propose to use our behavioral economics approach to extend the classical mono-drug addiction profile for cocaine abuse to poly-drug abuse, and examine the propensity of a negative allostatic state produced by chronic alcohol exposure and withdrawal to aggravate cocaine abuse. Several studies have linked excessive motivation for drug to a negative allostatic state, often resulting from chronic drug exposure and withdrawal. Cocaine is thought to be more reinforcing during this new allostatic state, which leads to increased craving for drug and relapse. Here, we hypothesize that chronic exposure and withdrawal from alcohol can lead to a negative allostatic state that increases cocaine demand and facilitates the transition to a cocaine addiction phenotype. As in the original R01 application, we propose that this potentiation of cocaine addiction involves the orexin (hypocretin) brain system. Recent studies show that orexin plays a major role in motivation for cocaine; our findings indicate that this reflects a role in cocaine essential value (demand under high-effort conditions). Work by us and others shows that orexin also is critical for alcohol preference and relapse to alcohol seeking in a variety of paradigms. This joint dependence of both cocaine and alcohol seeking on orexin signaling led to the current hypothesis that alcohol exposure may engage orexin systems to facilitate a transition to a cocaine addiction phenotype. Here, we will apply specific manipulations of orexin neurons in rats during behavioral economics paradigms to analyze orexin’s role in cocaine demand after chronic alcohol exposure, and to examine the influence of alcohol on cocaine abuse and the role of orexin in this interaction. Positive results with these experiments would lead to novel orexin-based therapeutics for alcohol potentiation of cocaine addiction, and for polydrug abuse in general. Project


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