Early-Life Stress Drives Increased Heroin Vulnerability: Role of D3 Receptors

项目摘要 压力和成瘾是错综复杂的神经过程。急性压力可以作为复发的刺激， 戒断后强迫性药物寻求，慢性压力可导致药物摄入量增加到多个 毒品的种类琼斯实验室和其他人已经表明，青少年的慢性心理社会压力源 社会隔离（aSI）导致中脑核（NAc）中多巴胺（DA）功能受损， 对刺激性药物和酒精的脆弱性增加，持续到成年。但不清楚 aSI如何影响阿片类药物的消耗。在目前的建议中，我已经证明了aSI导致了一个强大的 海洛因自我给药、复吸倾向和海洛因戒断引起负面影响增加。 aSI大鼠对海洛因的易感性增加，同时有数据显示， 多巴胺的功能比aGH动物，可能会推动这种增加海洛因行为在aSI动物。F99 本提案的第一阶段将主要研究多巴胺D3自身受体（D3autoR）在NAc中的作用， 在aSI大鼠中，驾驶增加了海洛因的脆弱性并减少了多巴胺的传递。我假设 aSI应激和海洛因自我给药的组合协同增加D3autoR介导的 中脑边缘DA系统的适应产生多巴胺能减退症，增加海洛因使用的脆弱性。 拟议的项目还将帮助候选人布里安娜乔治女士实现她的职业目标，成为 一个研究密集型机构的独立调查员。该项目提供培训， 研究技术，包括快速扫描循环伏安法，RNAscope和基因沉默。此夕h 建议的研究将提供专业和技术培训，以准备候选人成功地 过渡到博士后职位（K00）在一个实验室，研究神经电路驱动的脆弱性， 吸毒行为。这里为F99和K00阶段提出的完整计划已经设计完成。 培养一个独立的神经生物学家准备过渡到一个成功的博士后职位， 最终成为独立的终身研究员

PROJECT SUMMARY Stress and addiction are intricately linked neural processes. Acute stress can serve as a stimulus for relapse to compulsive drug seeking following abstinence, and chronic stress can induce escalated drug intake to multiple classes of drugs. The Jones lab and others have shown that the chronic psychosocial stressor of adolescent social isolation (aSI) leads to impairments in dopamine (DA) function in the nucleus accumbens (NAc) and increased vulnerability to stimulant drug and alcohol taking that persists into adulthood. However, it is unknown how aSI affects consumption of opioids. In the current proposal, I have demonstrated that aSI leads to a robust increase in heroin self-administration, propensity for relapse, and heroin withdrawal-induced negative affect. This increase in vulnerability to heroin in aSI rats was coupled with data showing a greater reduction of dopamine function than aGH animals that may drive this increase in heroin behaviors in aSI animals. The F99 phase of this proposal will primarily examine the role dopamine D3 autoreceptor (D3autoR) in the NAc in driving increased heroin vulnerability and reduced dopamine transmission in aSI rats. I hypothesize that the combination of aSI stress and heroin self-administration synergistically increase D3autoR-mediated adaptations in the mesolimbic DA system producing hypodopaminergia and increasing heroin use vulnerability. The proposed project will also help the candidate, Ms. Brianna George, achieve her career goal of becoming an independent investigator at a research-intensive institution. This project provides training in valuable research techniques, including fast-scan cyclic voltammetry, RNAscope, and gene silencing. Further, the proposed studies will provide professional and technical training to prepare the candidate to successfully transition to a postdoctoral position (K00) in a laboratory that studies the neural-circuitry driving vulnerability to drug-seeking behavior. The complete plan proposed here for both the F99 and K00 phases has been designed to develop an independent neurobiologist prepared for a transition to a successful postdoctoral position and, ultimately, independent tenured investigator.