Exercise as a Sex-Specific Intervention Strategy for Cocaine Addiction

 描述（由申请人提供）：长期药物暴露后发生的长期神经适应性和表观遗传变化被认为是成瘾特征的持续行为变化的基础。因此，治疗成瘾的一个策略是专注于可以逆转这些变化的干预措施，这在理论上可以将成瘾过程逆转到一个不再强迫寻求药物的水平。我们最近证明，禁欲期间的运动是一种干预措施，能够逆转/阻断与复发脆弱性相关的药物诱导的神经适应。本R 01提案的目标是确定运动作为可卡因成瘾干预的有效性机制，重点是前额叶皮层（PFC）中脑源性神经营养因子（BDNF）的表观遗传调节。BDNF是在人类和动物模型中与复发易感性正相关的少数标志物之一。有证据表明，在早期可卡因戒断期间，当水平较低时，增加BDNF可以防止其随后的增加以及复发脆弱性的增加。已知运动既能增加BDNF又能减弱可卡因寻求，有证据表明运动通过BDNF外显子IV的表观遗传调节发挥这些作用。值得注意的是，我们发现，车轮运行，运动的动物模型，在早期禁欲剂量依赖性降低随后的可卡因寻求和BDNF外显子IV的PFC中的表达。我们最近的数据还显示，运动的时间依赖性影响，在早期禁欲，但不是在后来的禁欲，它有效地减少了随后的可卡因寻求。因此，我们假设，运动，通过表观遗传调控，块可卡因诱导的BDNF的减少，在早期禁欲期间观察到，从而防止代偿性神经适应，导致增强可卡因寻求。基于我们最近的研究结果表明，运动在减少可卡因寻求的功效在男性和女性之间以及在不同激素状态的女性中存在差异，我们进一步假设运动对BDNF信号传导和重塑的影响的性别和性别特异性差异是其功效的基础。这些假设将使用可卡因复吸的动物模型进行测试，其中在长期可卡因自我给药后，可卡因寻求增加或潜伏，超过长期禁欲。为了实现我们的目标，在目标1中，我们将首先确定与不同激素状态下男性和女性的孵化效应相关的BDNF信号传导和重塑的标志物，然后在目标2中，我们将确定运动对这些变化的影响。最后，为了建立运动功效的因果机制，在目标3中，我们将评估PFC BDNF单独和结合运动的位点特异性操作的效果。这是一个研究不足的领域，研究结果将大大有助于我们理解，不仅运动是可卡因成瘾的性别特异性干预，而且性和卵巢激素如何影响成瘾和恢复的过程。

 DESCRIPTION (provided by applicant): Long-term neuroadaptive and epigenetic changes that develop following chronic drug exposure are believed to underlie persistent behavioral changes that characterize addiction. Thus, one strategy for treating addiction is to focus on interventions that can reverse these changes, which would theoretically reverse the addiction process back to a level where the individual is no longer compulsively seeking drugs. We recently demonstrated that exercise during abstinence is one type of intervention that is able to reverse/block drug- induced neuroadaptations associated with relapse vulnerability. The goal of this R01 proposal is to determine the mechanism for the efficacy of exercise as an intervention for cocaine addiction focusing on epigenetic regulation of brain-derived neurotrophic factor (BDNF) in the prefrontal cortex (PFC). BDNF is one of the few markers that positively associates with relapse vulnerability in both humans and animal models. Evidence indicates that increasing BDNF during early cocaine abstinence, when levels are low, prevents its subsequent increase as well as the increase in relapse vulnerability. Exercise is known to both increase BDNF and to attenuate cocaine-seeking, with evidence to suggest that it exerts these effects through epigenetic regulation of Bdnf exon IV. Notably, we showed that wheel running, an animal model of exercise, beginning during early abstinence dose-dependently reduced subsequent cocaine-seeking and Bdnf exon IV expression in the PFC. Our recent data also show time-dependent effects of exercise where during early abstinence, but not during later abstinence, it effectively reduced subsequent cocaine-seeking. Therefore, we hypothesize that exercise, through epigenetic regulation, blocks cocaine-induced decreases in BDNF that are observed during early abstinence, thus preventing compensatory neuroadaptations that lead to enhanced cocaine-seeking. Based our recent findings showing that the efficacy of exercise at reducing cocaine-seeking differs between males and females and in females at different hormonal states, we further hypothesize that sex and hormone-specific differences in the effects of exercise on BDNF signaling and remodeling underlie its efficacy. These hypotheses will be tested using an animal model of cocaine relapse wherein following chronic cocaine self-administration, cocaine-seeking increases, or incubates, over protracted abstinence. To accomplish our goals, in Aim 1 we will first determine the markers of BDNF signaling and remodeling that are associated with the incubation effect in males and in females at different hormonal states, and then in Aim 2 we will determine the effects of exercise on these changes. Finally, in order to establish a causal mechanism for the efficacy of exercise, in Aim 3 we will assess the effects of site-specific manipulation of PFC BDNF alone and in combination with exercise. This is an understudied area of research and the results will greatly contribute to our understanding of not only exercise as a sex-specific intervention for cocaine addiction, but also how sex and ovarian hormones influence the process of addiction and recovery.