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

基本信息

批准号：
10669480
负责人：
Cassandra D Gipson-Reichardt
金额：
$ 61.46万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-30 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10669480
关键词：
Acetylcysteine Animals Attenuated Biological Markers Brain Chemosensitization Chronic Clinical Cocaine Cocaine use disorder Cocaine withdrawal Cues Dendritic Spines Dependence Development 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

项目摘要

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）是美国主要的公共卫生危机。使用阿片类药物的人障碍经常使用其他物质，包括可卡因。去年阿片类药物戒断与 4 目前使用可卡因的几率增加了一倍，这可能代表着改善阿片类药物戒断的尝试临床前和临床研究结果证明，这种药物不仅会产生影响，还会增加用药过量的风险。批准的 OUD 药物疗法有一定效果，但这些药物不适用于治疗可卡因共同使用，强调需要一种新的干预方法来改善共病 OUD 和可卡因使用的结果紊乱。从机制上讲，药物驱动的行为是由皮质纹状体内的谷氨酸信号调节的电路。阿片类药物和可卡因自我给药 (SA) 均下调神经胶质谷氨酸转运蛋白 (GLT- 1)，并通过树突棘和 AMPA 与 NMDA 电流比率的变化来改变突触可塑性 (A/N) 在伏隔核核心 (NAcore) 内。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机制。阿片类药物和阿片类药物的综合作用然而，可卡因对谷氨酸能系统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（包括可卡因和阿片类药物）的转化前景。 NAC有能力恢复由任一药物单独引起的谷氨酸改变，可能是通过增加谷氨酸清除率通过上调 GLT-1 来调节药物使用后的突触。临床上，我们已经证明 NAC 可以减少可卡因相关刺激的显着性，控制着药物寻求。同样，其他人也表明 NAC 使可卡因依赖者的谷氨酸功能正常化。 NAC是否减少药物摄入并逆转同时使用阿片类药物和可卡因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。我们的首要假设是（1）持久性脑谷氨酸长期使用阿片类药物引起的变化将加剧阿片类药物身体依赖期间可卡因的使用， (2) NAC 将改善谷氨酸能失调，从而减少羟考酮和可卡因的使用。我们提出了一个由 R21/R33 机制支持的两阶段转化项目。在第一阶段（R21），我们将表征阿片类药物和可卡因共同使用中的 NAcore 谷氨酸信号传导作为神经网络使用临床前实验室方法以 NAC 为药物治疗靶向的生物标志物。见面后为 R21 设定的里程碑，我们将进行第二阶段（R33），其中我们将确定影响力 NAC 对阿片类药物和可卡因使用障碍共病中谷氨酸功能和可卡因的增强作用使用人类实验室方法。该转化项目期间完成的里程碑将阐明阿片类药物和可卡因共同使用导致谷氨酸能失调，为有效治疗奠定了基础通过针对谷氨酸信号传导对这种多物质滥用模式进行药物治疗。