The effect of ethanol self-administration on cocaine reinforcement in male and female monkeys

In the U.S., substance use disorders (SUDs) cost more than $820 billion dollars a year and continue to present significant challenges to health and justice systems [1, 2]. Although there are clinically effective pharmacotherapies for numerous drugs of misuse there are currently no FDA-approved treatments for cocaine use disorder (CUD), despite decades of preclinical research. The lack of effective medications for CUD suggests that there are gaps in translatability between preclinical and clinical research. One possible cause of this gap is the fact that most individuals with CUD are using more than one drug at the same time [3]. One substance that is commonly co-used with cocaine is alcohol and estimates suggest that up to 90% of individuals who misuse cocaine also co-use alcohol [4, 5]. While the mechanistic basis of alcohol and cocaine co-use is still poorly understood, research suggests that ethanol may enhance cocaine’s elevation of striatal dopamine concentrations, thus increasing cocaine’s reinforcing effects [6]. It is also important to note that the co-use of cocaine and alcohol is associated with more severe cocaine dependence, higher rates of psychiatric co-morbidities, and poorer treatment outcomes [7-9]. Despite this, the vast majority of substance abuse research has focused on the use of cocaine or alcohol in isolation, which may limit the clinical translatability of research findings. Given this, the aims of this NRSA are to characterize the effects of ethanol on vulnerability to cocaine reinforcement (Aim 1), to examine how ethanol influences maladaptive cocaine choice in the presence of an alternative reinforcer (Aim 2), and to explore a potential pharmacotherapy for cocaine and alcohol co-use (Aim 3) in a translational nonhuman primate model of substance use. I hypothesize that ethanol consumption will enhance the potency of cocaine reinforcement, resulting in greater sensitivity in studies of acquisition and the ability of alternative non-drug reinforcers to decrease cocaine choice. I also hypothesize that a combination of modafinil analog JJC8-091 and naltrexone will reduce both cocaine and ethanol self-administration. These findings will build on other data providing evidence as to why people co-use multiple drugs (e.g., enhance reinforcement) and how the study of pharmacological interventions need to consider these conditions.