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. Two decades ago, seminal studies in chronic cocaine abusers (Volkow 1992, 1993) identified resting- state reductions in prefrontal cortical (PFC) glucose metabolism (as measured by [18F]-FDG PET) during states of sustained drug abstinence (> 1 week and up to 3 months). These deficits in neuroenergetics are believed to account for the neurocognitive impairments that underlie the impulsive actions, compulsive behaviors, and risky decisions that lead to relapse in cocaine addicts. Despite their clinical importance, the molecular basis of these deficits is still unknown today. The current exploratory-developmental R01 seeks to directly test whether deficits in PFC glucose metabolism are reflective of abnormal glutamate neurotransmission in light of: 1) data demonstrating the direct neurometabolic coupling of cortical glucose metabolism and glutamatergic neurotransmission (Belanger 2011); 2) the unique ability of isotopic ([13C]-glucose) magnetic resonance spectroscopy (13C- MRS) to simultaneously and noninvasively assess neuroenergetics (mitochondrial glucose oxidation or VTCA) and glutamatergic neurotransmission (glutamate-glutamine cycling or VCYC) in humans (Rothman 2011), and 3) preclinical evidence demonstrating the importance of dysregulated glutamate homeostasis in cocaine- and cue-induced reinstatement of drug-seeking (Kalivas 2009). If confirmed, the current study would set the stage for future prospective, controlled, biomarker-guided (VCYC) evaluations of candidate pharmacotherapies (e.g., N-acetylcysteine, ceftriaxone, riluzole and/or pentoxifylline) targeted at restoring glutamate homeostasis (i.e., based on up-regulation of glial proteins, such as GLT-1, that mediate glutamate cycling / neurometabolic coupling).
As of today, there are no FDA-proved medication for cocaine addiction, including one that targets the problem of relapse. Basic science research has suggested 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 (as measured by [13C]-glucose magnetic resonance spectroscopy or 13C-MRS) are present in human cocaine abusers, setting the stage for future investigations of potentially new medications for preventing relapse.
