Exercise as a Sex-Specific Intervention Strategy for Cocaine Addiction

运动作为针对可卡因成瘾的针对性别的干预策略

• 批准号: 9015422
• 负责人: Wendy Jean Lynch
• 金额: $ 34.49万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2020-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9015422
• 关键词: Abstinence; Acetylation; Animal Model; Area; Attenuated; Award; Back; Behavioral; Brain; Brain-Derived Neurotrophic Factor; Chronic; Cocaine; Cocaine Dependence; Cues; Data; Development; Dose; Down-Regulation; Drug Exposure; Epigenetic Process; Estrogens; Exercise; Exons; Female; Genetic Transcription; Goals; Gonadal Steroid Hormones; Health; Hormonal; Human; Incubated; Individual; Intervention; Lead; Mediating; Methyl-CpG-Binding Protein 2; Mitogen-Activated Protein Kinases; Modeling; Ovarian hormone; Pharmaceutical Preparations; Prefrontal Cortex; Process; Rattus; Recovery; Relapse; Research; Running; Self Administration; Signal Transduction; Site; Testing; Time; Up-Regulation; Woman; addiction; base; cocaine relapse; epigenetic regulation; male; men; neuroadaptation; prevent; sex

 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.

 描述（由申请人提供）：长期接触药物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，治疗成瘾的一种策略是专注于可以逆转这些变化的干预措施。从理论上讲，可以将成瘾过程逆转回个体不再强迫性寻求药物的水平。我们最近证明，戒断期间的锻炼是一种干预措施，能够逆转/阻止与复发相关的药物诱导的神经适应。该 R01 提案的目标是确定运动作为可卡因成瘾干预措施的功效机制，重点关注前额皮质 (PFC) 中的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，很少有与复发易感性呈正相关的标志物，证据表明，在早期可卡因戒断期间，当水平较低时，BDNF 的增加可以防止其随后的增加，并且众所周知，运动也会增加复发易感性。 BDNF 并减弱可卡因寻求，有证据表明它通过 Bdnf 外显子 IV 的表观遗传调控发挥这些作用。值得注意的是，我们表明，在早期戒断期间开始的轮跑运动，剂量依赖性地减少了随后的可卡因。我们最近的数据还显示了运动的时间依赖性影响，在早期戒断期间，但在后期戒断期间，它有效地减少了随后的可卡因寻求。因此，我们认为运动通过表观遗传调控，可以阻断早期戒断期间观察到的可卡因诱导的 BDNF 减少，从而防止导致可卡因寻求增强的代偿性神经适应。根据我们最近的研究结果表明，运动可以有效减少可卡因。 -寻求男性和女性之间以及处于不同激素状态的女性中的差异，我们进一步探究运动对 BDNF 信号传导和重塑的影响的性别和激素特异性差异是其功效的基础。这些假设将使用动物进行测试。为了实现我们的目标，在目标 1 中，我们将首先确定与潜伏效应相关的 BDNF 信号传导和重塑标记。在不同荷尔蒙状态下的男性和女性中，然后在目标 2 中，我们将确定运动对这些变化的影响，最后，为了在目标 3 中建立运动功效的因果机制。我们将评估单独对 PFC BDNF 进行位点特定操作以及与运动相结合的效果，这是一个尚未充分研究的研究领域，其结果将极大地有助于我们理解运动不仅是可卡因的性别特异性干预措施。成瘾，以及性和卵巢激素如何影响成瘾和恢复的过程。