Glutamergic Mechanisms in Opioid and Cocaine Co-Use

阿片类药物和可卡因共同使用的谷氨酸机制

• 批准号: 10264811
• 负责人: Cassandra D Gipson-Reichardt
• 金额: $ 18.86万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-30 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10264811
• 关键词: Acetylcysteine; Animals; Attenuated; Biological Markers; Brain; Chemosensitization; Chronic; Clinical; Cocaine; Cues; Dendritic Spines; Dependence; Development; Disease; Dose; Drug Controls; Drug Use Disorder; Drug usage; Food; Glutamate Transporter; Glutamates; Heroin; Homosynaptic Depression; Human; Individual; Intake; Intervention; Intravenous; Knowledge; Laboratories; Magnetic Resonance Spectroscopy; Maintenance; Measures; Methods; Modeling; Motivation; N-Methylaspartate; Neurons; Nucleus Accumbens; Opioid; Opioid agonist; Oral; Oxycodone; Pattern; Pharmaceutical Preparations; Pharmacotherapy; Phase; Phased Innovation Awards; Physical Dependence; Physiological; Placebos; Proteins; Protocols documentation; Proxy; Public Health; Randomized; Reporting; Self Administration; Specific qualifier value; Stimulus; Synapses; Synaptic plasticity; System; Time; United States; Up-Regulation; Withdrawal; Work; cocaine exposure; cocaine self-administration; cocaine use; comorbidity; comparison group; experience; glutamatergic signaling; improved outcome; incentive salience; meetings; motivated behavior; multiple drug use; neurobiological mechanism; neuromechanism; novel; novel therapeutics; opioid use; opioid use disorder; opioid withdrawal; overdose risk; polysubstance abuse; pre-clinical; protein expression; relating to nervous system; sex

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.

阿片类药物使用障碍（OUD）是美国领先的公共卫生危机。患有阿片类药物的人 疾病经常使用其他物质，包括可卡因。过去的阿片类药物提取与4相关 当前可卡因使用的几率更大，这可能代表了改善阿片类药物的尝试 临床前和临床发现证明了影响，但也会增加过量的风险。批准的Oud 药物疗法是适度有效的，但是这些药物并未用于治疗可卡因共同使用， 强调需要采用新颖的干预方法来改善联合使用和可卡因的结局 紊乱。从机械上讲，药物动机行为受皮质纹状体内的谷氨酸信号传导调节 电路。阿片类药物和可卡因自我给药（SA）都下调了神经胶质谷氨酸转运蛋白（GLT- 1），并在树突状刺和AMPA与NMDA电流比的变化中测量的改变突触可塑性 （A/N）在伏隔核（Nacore）内。因此，谷氨酸能塑性是一种保守的神经 阿片类药物和可卡因使用的药物动机的基础机制。阿片类药物和 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 治疗多种药物使用障碍的转化诺言，包括可卡因和阿片类药物。 NAC有能力 仅通过增加任何一种药物引起的谷氨酸能改变，可能是通过增加谷氨酸清除率 通过上调GLT-1，药物使用后的突触。临床上，我们已经表明NAC减少了 可卡因相关刺激的激励显着性，该刺激控制着药物寻求药物。同样，其他人也表明了NAC 使可卡因依赖性个体中的谷氨酸功能归一化。 NAC是否减少药物摄入量并逆转 阿片类药物和可卡因共同使用引起的谷氨酸能改变是未知的。这里提出的工作将 开始填补那些关键的知识差距。我们的总体假设是（1）持续的脑谷氨酸 慢性阿片类药物诱导的变化将加剧阿片类物理依赖性可卡因的使用，并且 戒断和（2）NAC会改善谷氨酸能失调，从而减少两个羟考酮 和可卡因的使用。我们提出了一个由R21/R33机制支持的两阶段的转化项目。在 第一阶段（R21），我们将表征阿片类药物和可卡因中的Nacore谷氨酸能信号传导作为神经 使用临床前实验室方法对NAC进行药物治疗靶向的生物标志物。见面 为R21提出的里程碑，我们将进行第二阶段（R33），在其中我们将确定影响的影响 NAC对谷氨酸功能以及可卡因在合并症阿片类药物和可卡因使用障碍中的增强作用 使用人类实验室方法。在这个翻译项目中完成的里程碑将阐明 谷氨酸能失调的阿片类药物和可卡因共同使用，为有效的基础奠定了基础 通过靶向谷氨酸信号传导，对这种滥用多物质滥用模式的药物治疗。