Dopaminergic and Glutamatergic Mechanisms of Cocaine Addiction: Sex Differences

描述（由申请方提供）：原始申请的总体目标是确定在男性和女性中产生可卡因寻求和服用行为进行性增加或潜伏期的条件，这些行为发生在从扩展访问自我给药中戒断后，并表征基础神经生物学。在这篇补充文章中，我们将通过考察阻碍这种“孵化效应”的条件来扩展最初的应用。具体来说，在本补充，我们将测试的假设，有氧运动（即，轮运行）将防止可卡因渴望的潜伏期和延长的可卡因自我施用后的相关神经适应的发生。因此，本补充的主要目标是确定运动作为复发期间干预的潜在效用。作为次要目标，我们还将确定有氧运动对禁欲期间发生的潜在神经生物学变化的影响，与最初的应用一样，我们将重点关注伏隔核和内侧前额叶皮质中多巴胺能和谷氨酸能信号传导的神经适应，这两个区域与可卡因成瘾有关。鉴于已知的男性和女性之间的差异，在时间过程中的发展成瘾，并根据一个新兴的文献，强调需要使用性别特异性干预措施，第三个目标是确定男性和女性是否有不同的反应运动作为一种干预。这个应用程序有一个特定的目标，被视为原始应用程序的第四个目标。具体来说，这种补充剂的目的是确定有氧运动对可卡因复吸及其潜在神经生物学的影响，作为性别和激素状态的函数。为了实现这一目标，在延长的可卡因自我给药和延长的戒断期后，将在线索诱导和应激诱导的条件下检查可卡因恢复，其中大鼠将有2小时/轮或没有轮。多巴胺的标志物（即，酪氨酸羟化酶和多巴胺和cAMP调节的32 kDa磷蛋白（DARPP-32）的总水平和磷酸化水平），谷氨酸（即，NR 1和GluR 1的总水平和磷酸化水平），以及细胞外信号调节激酶信号传导将在延长接触可卡因后2周在大鼠的脑桥核和内侧前额叶皮层中使用Western印迹分析进行检查。作为拟议研究的一部分，我们计划将行为，激素和分子化学数据相关联，以帮助确定可能延缓可卡因复吸的生物学特征。这些拟议的补充研究对父母补助金的既定最终目标进行了测试，以确定可针对男女的潜在干预措施。 公共卫生相关性：我们的研究意义重大，因为它侧重于确定运动作为男性和女性可卡因成瘾的潜在干预措施的功效和生物学基础。这项基础科学工作的总体目标是帮助确定运动是否是对可卡因成瘾的有效干预，并提供可能指导制定更有效的性别特异性干预措施的信息。

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.