Prescription Opioid Addiction: Neurobiological Mechanisms

处方阿片类药物成瘾：神经生物学机制

• 批准号: 8811924
• 负责人: LOREN H. PARSONS
• 金额: $ 42万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-03-01 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8811924
• 关键词: Admission activity; Amygdaloid structure; Analgesics; Animal Model; Animals; Brain; Brain region; Buprenorphine; Centers for Disease Control and Prevention (U.S.); Cessation of life; Chronic; Cocaine; Corticotropin-Releasing Hormone; Dependence; Development; Drug Kinetics; Drug Prescriptions; Drug abuse; Dynorphins; Emergency department visit; Endocytosis; Epidemic; Etiology; FarGo; Future; Gene Silencing; Health; Heroin; Homeostasis; Hydrocodone; In Vitro; Individual; Individual Differences; Intake; Knowledge; Medicine; Microinjections; Morphine; Neurobiology; Neurons; Opiate Addiction; Opioid; Opioid Analgesics; Opioid Peptide; Opioid Receptor; Oxycodone; Pharmaceutical Preparations; Pharmacodynamics; Pharmacologic Substance; Prevention; Rattus; Relative (related person); Rewards; Self Administration; Signal Transduction; Smoke; Stress; Subgroup; System; Testing; United States Substance Abuse and Mental Health Services Administration; Ventral Striatum; Viral Vector; Withdrawal; addiction; aged; base; disorder prevention; hedonic; insight; knock-down; neuroadaptation; neurobiological mechanism; novel; opioid abuse; overdose death; prescription opioid; prescription opioid abuse; receptor; relating to nervous system; response

DESCRIPTION (provided by applicant): A major and growing problem in the field of drug abuse is prescription opioid abuse and dependence, which has reached epidemic proportions. A major question is whether there are any unique pharmacodynamics or neuroadaptations to explain this epidemic. One largely unexplored hypothesis to explain the high abuse potential of the prescription opioid medicines such as oxycodone is that there are neurobiological vulnerabilities in response to chronic administration of these drugs that predispose individuals to addiction on such opioids and that these neurobiological vulnerabilities are exaggerated by the pharmacodynamics of certain synthetic opioids. To test this hypothesis, in the present proposal, individual differences in compulsive drug seeking and dependence will be correlated with individual neuroadaptational changes in brain stress systems known to drive dependence. In Specific Aim 1, animal models of compulsive drug seeking and dependence will be developed for oxycodone and compared to drug seeking for heroin and buprenorphine. Using such animal models, individual differences in compulsive drug seeking, withdrawal and re-escalation of compulsive drug seeking will be characterized. In parallel, in Specific Aim 2 dysregulation of neural systems known to drive the development of compulsive opioid seeking will be characterized. These include alteration of the brain corticotropin releasing factor (CRF) systems and brain dynorphin kappa systems in brain reward and stress circuits. Finally, in Specific Aim 3 microinjection of antagonists of the CRF system and the kappa system in specific brain regions and gene silencing of specific CRF and dynorphin neurocircuits will be employed to reverse neuroadaptive changes and consequent re-escalation of drug seeking in subgroups of rats with high levels of compulsive drug seeking. The present proposal will go far towards elucidating the neurobiological systems within specific neurobiological circuits of the ventral striatum and extended amygdala, which are critical for the motivational aspects of prescription opioid abuse and dependence. The present proposal also will provide important information for identifying novel non- mu opioid treatments for opioid addiction.

描述（由申请人提供）：药物滥用领域的一个主要和日益严重的问题是处方阿片类药物滥用和依赖，已达到流行病的比例。一个主要的问题是是否有任何独特的药效学或神经适应来解释这种流行病。解释羟考酮等处方阿片类药物高滥用可能性的一个基本上未探索的假设是，长期服用这些药物会导致神经生物学脆弱性，使个人容易出现以下情况： 这些神经生物学脆弱性被某些合成类阿片的药效学夸大。为了验证这一假设，在本提案中，强迫性药物寻求和依赖的个体差异将与已知驱动依赖的大脑压力系统中的个体神经适应性变化相关。在具体目标1中，将开发羟考酮的强迫性药物寻求和依赖动物模型，并与海洛因和丁丙诺啡的药物寻求进行比较。使用这种动物模型，将表征强迫性药物寻求、强迫性药物寻求的戒断和再升级的个体差异。与此同时，在特定目标2中，将描述已知驱动强迫性阿片类药物寻求发展的神经系统失调的特征。这些包括改变脑促肾上腺皮质激素释放因子（CRF）系统和脑强啡肽κ系统在大脑奖励和压力电路。最后，在特定目标3中，将采用在特定脑区域中微量注射CRF系统和kappa系统的拮抗剂以及特定CRF和强啡肽神经回路的基因沉默来逆转神经适应性变化以及随后在具有高水平强迫性药物寻求的大鼠亚组中药物寻求的重新升级。本提案将进一步阐明腹侧纹状体和扩展杏仁核的特定神经生物学回路内的神经生物学系统，这对于处方阿片类药物滥用和依赖的动机方面至关重要。本提案也将为确定阿片类药物成瘾的新型非μ阿片类药物治疗提供重要信息。