Glutamergic Mechanisms in Opioid and Cocaine Co-Use

Opioid use disorder (OUD) is a leading public health crisis in the United States. Individuals with opioid use disorder frequently use other substances, including cocaine. Past year opioid withdrawal was associated with 4 times greater odds of current cocaine use, which may represent an attempt to ameliorate opioid withdrawal effects but also increases overdose risk, as evidenced by preclinical and clinical findings. Approved OUD pharmacotherapies are modestly effective, but these medications are not indicated for treating cocaine co-use, highlighting the need for a novel intervention approach to improve outcomes in co-morbid OUD and cocaine use disorder. Mechanistically, drug-motivated behaviors are regulated by glutamate signaling within corticostriatal circuitry. Both opioid and cocaine self-administration (SA) down-regulate the glial glutamate transporter (GLT- 1), and alter synaptic plasticity measured as changes in dendritic spines and AMPA-to-NMDA current ratios (A/N) within the nucleus accumbens core (NAcore). Thus, glutamatergic plasticity is a conserved neural mechanism underlying drug motivation in both opioid and cocaine use. The combined effects of opioid and cocaine co-use on glutamatergic systems, however, are unknown. n-Acetylcysteine (NAC) has shown translational promise for treating multiple drug use disorders, including cocaine and opioids. NAC is capable of restoring glutamatergic alterations induced by either drug alone, likely by increasing glutamate clearance from the synapse following drug use through upregulation of GLT-1. Clinically, we have shown that NAC reduces the incentive salience of cocaine-related stimuli, which controls drug seeking. As well, others have shown that NAC normalizes glutamate function in cocaine-dependent individuals. Whether NAC reduces drug intake and reverses glutamatergic alterations induced by co-use of opioids and cocaine is unknown. The work proposed here will begin to fill those crucial knowledge gaps. Our overarching hypotheses are that (1) persistent brain glutamate changes induced by chronic opioid use will exacerbate use of cocaine during opioid physical dependence and withdrawal and (2) that NAC will ameliorate glutamatergic dysregulation, and thus will reduce both oxycodone and cocaine use. We propose a two phase, translational project supported by the R21/R33 mechanism. In the first phase (R21), we will characterize NAcore glutamatergic signaling in opioid and cocaine co-use as a neural biomarker for pharmacotherapeutic targeting with NAC using preclinical laboratory methods. Upon meeting the milestones set forth for the R21, we will conduct the second phase (R33), in which we will determine the influence of NAC on glutamate function and reinforcing effects of cocaine in co-morbid opioid and cocaine use disorder using human laboratory methods. The milestones completed during this translational project will elucidate glutamatergic dysregulation underlying opioid and cocaine co-use, laying the groundwork for effective pharmacotherapeutic treatment for this pattern of polysubstance abuse through targeting glutamate signaling.