Validation of a rat model of co-morbid cocaine and alcohol use

Smoking of cocaine base is one of the two most common routes of cocaine use in the United States. Smoking cocaine base achieves maximal concentration and effect more rapidly than intranasal cocaine intake, and it is associated with greater propensity for dependence, higher incidence of psychiatric comorbidities and worse treatment outcomes. Despite the prevalence of cocaine base use in humans and the health crisis it presents, this is an understudied area in basic science. Important for this proposal, cocaine use is highly co-morbid with alcohol use, and concurrent use of cocaine and alcohol leads to production of the bioactive metabolite cocaethylene. Here, we propose to develop and validate a novel preclinical model of cocaine base vapor inhalation that recapitulates core features of cocaine base use in humans, and to use this model to examine combined cocaine vapor inhalation and oral alcohol effects on behavior and physiology, as well as blood-drug and blood-metabolite levels in rats. The proposed aims will test the main predictions that oral alcohol consumption potentiates cocaine vapor inhalation effects, that vaporized cocaine base inhalation supports stable drug-taking behavior in rats, and that this behavior is modulated by concurrent (i.e., same-day) access to alcohol. This work will use a highly controllable system that delivers vaporized cocaine base to male and female rats on experimenter-determined and response-contingent schedules. The overall goal of this work is to develop a preclinical model of cocaine vapor inhalation that recapitulates core features of cocaine base use in humans and is useful for investigating 1) the physiological and behavioral effects of the inhaled drug, 2) the neurobiological basis of cocaine base use, and 3) the effects of co-exposure to cocaine vapor and other drugs (e.g., alcohol). The data generated in this study will support an R01 application that employs this novel, translationally relevant animal model to investigate the CNS effects of and cellular mechanisms underlying co-morbid cocaine base and alcohol use.