Glutamergic Mechanisms in Opioid and Cocaine Co-Use

阿片类药物使用障碍(OUD)是美国主要的公共健康危机。使用阿片类药物的个人 精神障碍患者经常使用其他物质，包括可卡因。过去一年的阿片类药物戒断与4 当前使用可卡因的几率更大，这可能代表着试图改善阿片类药物的戒断 临床前和临床研究结果表明，这不仅会产生副作用，还会增加过量用药的风险。批准的OUD 药物疗法是适度有效的，但这些药物并不是用于治疗可卡因联合使用， 强调需要一种新的干预方法来改善吸食可卡因和吸食可卡因共病的结果 无序。机制上，药物激发的行为受皮质纹状体内谷氨酸信号的调节 电路。阿片类药物和可卡因自身给药(SA)均下调神经胶质细胞谷氨酸转运体(GLT- 1)，并改变突触可塑性，以树突棘和AMPA/NMDA电流比率的变化来衡量 (A/N)位于伏隔核核心(NAcore)。因此，谷氨酸可塑性是一种保守的神经。 阿片类药物和可卡因使用中药物动机的潜在机制。阿片类药物和阿片类药物的联合作用 然而，可卡因在谷氨酸能系统上的共同使用尚不清楚。N-乙酰半胱氨酸(NAC)已显示 治疗包括可卡因和阿片类药物在内的多种药物使用障碍的翻译前景。南汽有能力 恢复由任何一种药物单独引起的谷氨酸能改变，可能是通过增加谷氨酸从 通过上调GLT-1而导致药物使用后的突触。临床上，我们已经证明NAC降低了 与可卡因相关的刺激的激励性显著，它控制着药物寻求。同样，其他人也表明，南汽 使可卡因依赖者的谷氨酸功能正常化。NAC是否会减少药物摄入量并逆转 阿片类药物和可卡因联合使用引起的谷氨酸能改变尚不清楚。这里提出的工作将 开始填补这些关键的知识空白。我们的主要假设是：(1)持久的大脑谷氨酸 长期使用阿片类药物引起的变化将加剧阿片类物质依赖期间可卡因的使用，并 戒断和(2)NAC可改善谷氨酸能失调，从而降低羟考酮 和可卡因的使用。我们提出了一个由R21/R33机制支持的两阶段翻译项目。在 第一阶段(R21)，我们将研究阿片类药物和可卡因共同用作神经的NAcore谷氨酸能信号 使用临床前实验室方法进行NAC药物治疗靶向的生物标志物。在会见了 为R21制定的里程碑，我们将进行第二阶段(R33)，在此阶段我们将确定影响 NAC对阿片类药物与可卡因使用障碍共病患者谷氨酸功能的影响及可卡因的强化作用 使用人类实验室的方法。在此翻译项目期间完成的里程碑将阐明 阿片类药物和可卡因联合使用下的谷氨酸能失调，为有效 通过靶向谷氨酸信号对这种多物质滥用模式的药物治疗。

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.