Relapse remains a critical unmet challenge in the treatment of cocaine addiction. While many will succeed in initiating abstinence, the vast majority of cocaine abusers will experience multiple relapses over the course of their illness, and many will fail to achieve an enduring drug-free existence. Thus, the current lack of medications for reducing relapse risk remains a major gap in the clinical management of cocaine dependence. A large body of basic research points to glutamate (GLU) as playing a central role in the neural adaptations to and reinstatement of repeated cocaine administration. In particular, preclinical work by Kalivas and colleagues has advanced a compelling model whereby dysregulated subcortical (i.e., nucleus accumbens or NAcc) GLU transmission accounts for the vulnerability to reinstated drug seeking in animals. The relevance of this GLU homeostasis hypothesis [14] for CD humans remains largely untested, however, due to the lack of clinical- translational tools capable of measuring GLU levels in the ventral striatum (VS) in humans. Innovations in high-field (7 Tesla), proton magnetic resonance spectroscopy (1H-MRS) by members of our research group now suggest the feasibility of obtaining direct measures of brain GLU in human VS. Thus, the current Exploratory/Developmental R21 application seeks to adapt and apply these advances to the development of a robust, practical, cost-effective, and objective biomarker of dysregulated GLU homeostasis in humans, one that can directly and efficiently inform the evaluation of candidate medications for CD patients. If achieved, the current study would set the stage for future prospective, controlled, biomarker-guided evaluations of candidate pharmacotherapies targeted at restoring GLU homeostasis on both a population, and even personalized medicine basis.
As of today, there are no FDA-proved medication for cocaine addiction, including one that targets the problem of relapse. Basic science research shows that cocaine causes abnormalities in an important neurotransmitter in the brain, glutamate, and that medications that restore glutamate function to normal, prevent relapse to cocaine-seeking behaviors in laboratory animals. The current study will test, for the first time in humans, whether abnormalities in glutamate function in a specific region of the brain (ventral striatum) as measured by 1H-magnetic resonance spectroscopy or 1H-MRS are present in human cocaine abusers and whether they are corrected by a promising medication for the disorder, N-acetylcysteine (NAC).
