Dopaminergic and Glutamatergic Mechanisms of Cocaine Addiction: Sex Differences

描述（由申请人提供）：原始申请的总体目标是确定在男性和女性中产生逐渐增加或潜伏的可卡因寻求和服用行为的条件，这些行为发生在戒断长期自我给药后，并描述潜在的神经生物学特征。在本增刊中，我们将通过研究阻碍这种“孵化效应”的条件，对最初的应用进行扩展。具体来说，在这篇补充文章中，我们将检验一个假设，即在戒断期间进行有氧运动（即轮式跑步）将防止在长时间自我给药后出现可卡因渴望和相关神经适应的潜伏期。因此，本补充的主要目的是确定运动作为复发期间干预措施的潜在效用。作为次要目标，我们还将确定有氧运动对戒断期间发生的潜在神经生物学变化的影响，并且像最初的应用一样，我们将重点关注伏隔核和内侧前额皮质中多巴胺能和谷氨酸能信号的神经适应，这两个区域与可卡因成瘾有关。鉴于已知男性和女性在成瘾发展的时间过程中存在差异，并且基于新兴文献强调需要使用针对性别的干预措施，第三个目标是确定男性和女性对运动作为干预措施的反应是否不同。这个应用程序有一个特定的目标，它被视为原始应用程序的第四个目标。具体来说，本补充的目的是确定有氧运动对可卡因恢复的影响及其潜在的神经生物学作为性别和激素状态的功能。为了实现这一目标，将在线索诱导和压力诱导的条件下，在长时间的可卡因自我给药和长时间的戒断期后，对大鼠进行可卡因恢复试验，在戒断期中，大鼠将有2小时/次接触转轮或不接触转轮。使用Western Blot分析方法检测大鼠长期接触可卡因后2周的伏隔核和内侧前额叶皮层中多巴胺（即酪氨酸羟化酶和多巴胺以及camp调节的32 kDa磷酸化蛋白的总和磷酸化水平）、谷氨酸（即NR1和GluR1的总和磷酸化水平）和细胞外信号调节的激酶信号的标志物。作为拟议研究的一部分，我们计划将行为、激素和分子数据联系起来，以帮助确定可能延缓可卡因复发的生物学特征。这些拟议的补充研究测试了父母补助的最终目标，以确定可以为男性和女性量身定制的潜在干预措施。

DESCRIPTION (provided by applicant): The overall goal of the original application is to determine in both males and females the conditions that produce a progressive increase, or incubation, of cocaine-seeking and taking behaviors that occur following abstinence from extended access self-administration and to characterize the underlying neurobiology. In this supplement, we will expand upon the original application by examining conditions that retard this "incubation effect". Specifically, in this supplement, we will test the hypothesis that aerobic exercise (i.e., wheel running) during abstinence will prevent the occurrence of incubation of cocaine-craving and associated neuroadaptations after extended access cocaine self-administration. Therefore, the primary goal of this supplement is to determine the potential utility of exercise as an intervention during relapse. As a secondary objective, we will also determine the effects of aerobic exercise on the underlying neurobiological changes that occur during an abstinence period, and like the original application, we will focus on neuroadaptations in dopaminergic and glutamatergic signaling in the nucleus accumbens and medial prefrontal cortex, two regions implicated in cocaine addiction. Given known differences between males and females in the time-course for the development of addiction, and based on an emerging literature that highlights the need the use of sex-specific interventions, a third objective is to determine if males and females respond differently to exercise as an intervention. This application has one specific Aim that is seen as the fourth aim to the original application. Specifically, the aim of this supplement is to determine the effects of aerobic exercise on cocaine reinstatement and its underlying neurobiology as a function of sex and hormonal status. To satisfy this aim, cocaine reinstatement will be examined under both cue-induced and stress-induced conditions following extended access cocaine self-administration and an extended abstinence period whereby rats will either have 2 hrs/access to a wheel or no access. Markers of dopamine (i.e., total and phosphorylated levels of tyrosine hydroxylase and dopamine and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32)), glutamate (i.e., total and phosphorylated levels of NR1 and GluR1), and extracellular signal-regulated kinase signaling will be examined in the nucleus accumbens and medial prefrontal cortex of rats 2-weeks after extended access cocaine using Western Blot analysis. As part of the proposed research, we plan to correlate behavioral, hormonal, and molechemical data to help identify biological characteristics that may retard cocaine relapse. These proposed supplemental studies test the stated ultimate goal of the parent grant to identify potential interventions that can be tailored for men and women. PUBLIC HEALTH RELEVANCE: Our study is significant because it focuses on determining efficacy and biological basis for exercise as a potential intervention for cocaine addiction in males and females. The overall goals of this basic science work is to help determine whether exercise would be a useful intervention for cocaine addiction, and to provide information that may guide the development of even more effective sex-specific interventions.