Prescription Opioid Addiction: Neurobiological Mechanisms

描述（由申请人提供）：处方阿片类药物滥用和依赖是药物滥用领域一个主要且日益严重的问题，已达到流行病的程度。一个主要的问题是是否有任何独特的药效学或神经适应性来解释这种流行病。解释处方阿片类药物（如羟考酮）高滥用可能性的一个很大程度上未被探索的假设是，长期服用这些药物会产生神经生物学脆弱性，使个体容易产生

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.