Integrating preclinical models to develop converging mechanistic data in co-occuring HIV and substance use

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Project Summary Cocaine use disorders (CUDs) are highly comorbid with HIV infection and are characterized by a high propensity to relapse even after protracted abstinence. With the success of antiretroviral therapies (ART), HIV-associated mortality has substantially declined, resulting in a growing population of chronically HIV-infected, ART treated adults in the United States. Both HIV infection and ART may interact with drug exposure to alter neurobiology, thus creating a behaviorally and biologically distinct condition and requiring novel, targeted pharmacotherapeutic strategies to reduce relapse to cocaine use. Relapse to drug use may be precipitated by drug craving. During protracted withdrawal from repeated cocaine exposure, cocaine-seeking behavior becomes progressively stronger, indicative of the “incubation of craving”. Development of strategies to reduce this craving have strong potential to reduce relapse-related behaviors. Thus, research in this proposal is designed to complement the parent award by investigating independent and combined effects of progressive HIV infection and daily ART treatment on the neurobehavioral sequelae of the incubation of cocaine craving. The corticostriatal glutamate system is a key regulator of relapse-related behavior. Disruption of glutamate homeostasis and neuroinflammation occur with exposure to either cocaine or HIV infection. However, the impact of combined protracted cocaine abstinence and HIV on neuroimmune function and glutamate system function is poorly understood. This proposal will investigate the behavioral and neurobiological interactions between HIV and incubated cocaine craving within key mesocorticolimbic structures that facilitate cocaine seeking (the medial prefrontal cortex (mPFC) and nucleus accumbens (NAc)). We will test the overarching hypothesis that protracted abstinence from cocaine interacts with HIV and ART to uniquely dysregulate glutamate homeostasis and neuroimmune function, leading to potentiation of cocaine-seeking behavior. Aim 1 will determine the outcomes of EcoHIV infection and daily ART treatment on cocaine craving in a cocaine conditioned place preference model in male and female mice. Aim 2 will determine the effect of EcoHIV and daily ART on changes in glutamate system markers and neuroimmune function in the mPFC and NAc. Findings from these studies will complement the experiments outlined in the parent award and inform future research directions aimed at elucidating novel pharmacotherapeutic targets for the treatment of substance use disorders in the context of progressive HIV and ART. Further, the award of this administrative supplement will allow the candidate – an exceptionally well- qualified Hispanic-Asian postdoctoral scholar - to gain hands-on training in models of comorbid progressive HIV and cocaine exposure. Findings from the award are expected to serve as the basis for the development of an independent line of research that will lead to subsequent fellowship and career transition award proposals by the candidate.