Prescription Opioid Addiction: Neurobiological Mechanisms

处方阿片类药物成瘾：神经生物学机制

基本信息

批准号：
9024499
负责人：
MICHAEL A. TAFFE
金额：
$ 42.21万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
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/9024499
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 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

项目摘要

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且日益严重的问题是处方阿片类药物滥用和依赖，其已达到流行程度。一个主要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。解释处方阿片类药物（如羟考酮）的高滥用可能性的一个很大程度上尚未探索的假设是，长期服用这些药物存在神经生物学脆弱性，使个人容易出现对此类阿片类药物成瘾，并且某些合成阿片类药物的药效学夸大了这些神经生物学脆弱性。为了检验这一假设，在本提案中，强迫性药物寻求和依赖性的个体差异将与已知会驱动依赖性的大脑应激系统的个体神经适应变化相关。在具体目标 1 中，将为羟考酮开发强迫性药物寻求和依赖的动物模型，并将其与海洛因和丁丙诺啡的药物寻求进行比较。使用此类动物模型，将表征强迫性药物寻求、戒断和强迫性药物寻求的重新升级的个体差异。与此同时，在具体目标 2 中，将描述已知可驱动强迫性阿片类药物寻求发展的神经系统失调。其中包括大脑奖励和压力回路中大脑促肾上腺皮质激素释放因子（CRF）系统和大脑强啡肽卡帕系统的改变。最后，在特定目标 3 中，将在特定大脑区域显微注射 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，以逆转神经适应性变化以及随后在患有以下疾病的大鼠亚组中重新升级药物寻求：高度强迫性寻求毒品。本提案将进一步阐明腹侧纹状体和扩展杏仁核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。本提案还将为识别阿片类药物成瘾的新型非 mu 阿片类药物治疗提供重要信息。