Exercise as a Sex-Specific Intervention Strategy for Cocaine Addiction

 描述(由申请者提供)：长期的神经适应性和表观遗传学改变是慢性药物暴露后发展的基础，被认为是成瘾特征的持续性行为改变的基础。因此，治疗成瘾的一种策略是专注于能够逆转这些变化的干预措施，从理论上讲，这将使成瘾过程回到个人不再强制寻求毒品的水平。我们最近证明，禁欲期间的锻炼是一种能够逆转/阻止与复发易感性相关的药物诱导的神经适应的干预类型。这个R01提案的目的是确定运动作为可卡因成瘾干预的有效性的机制，重点是前额叶皮质(PFC)脑源性神经营养因子(BDNF)的表观遗传调节。在人类和动物模型中，BDNF是少数几个与复发易感性呈正相关的标志物之一。有证据表明，在可卡因戒断早期增加脑源性神经营养因子，在水平较低的情况下，可以防止随后的增加以及复发易感性的增加。众所周知，运动既可以增加BDNF，也可以减弱寻求可卡因，有证据表明，它是通过对BDNF外显子IV的表观遗传调节来发挥这些作用的。值得注意的是，我们发现，在戒断早期开始的运动动物模型--车轮跑步，可以剂量依赖地减少随后的可卡因寻求和BDNF外显子IV在PFC中的表达。我们最近的数据还显示了锻炼的时间依赖效应，在早期戒酒期间，但在后来的戒毒期间，锻炼有效地减少了随后的可卡因寻求。因此，我们假设，通过表观遗传调节，运动可以阻止可卡因诱导的BDNF减少，这是在戒酒早期观察到的，从而防止了导致寻求可卡因增加的代偿性神经适应。根据我们最近的发现，运动在减少可卡因寻求方面的有效性在男性和女性之间以及不同荷尔蒙状态的女性之间存在差异，我们进一步假设，运动对脑源性神经营养因子信号和重塑的影响中的性别和激素特异性差异是其有效性的基础。这些假说将使用可卡因复发的动物模型进行验证，在该模型中，在长期戒除可卡因后，寻求可卡因的人数增加或孵化。为了实现我们的目标，在目标1中，我们将首先确定与男性和女性在不同激素状态下的孵化效应相关的BDNF信号和重塑的标记物，然后在目标2中，我们将确定运动对这些变化的影响。最后，为了建立运动疗效的因果机制，在目标3中，我们将评估单独的部位特异性操作PFC BDNF以及与运动相结合的效果。这是一个研究不足的领域，其结果将极大地有助于我们理解运动不仅是对可卡因成瘾的性别特异性干预，而且还包括性激素和卵巢激素如何影响成瘾和康复过程。

 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.