Dopaminergic and Glutamatergic Mechanisms of Cocaine Addiction: Sex Differences

描述(由申请人提供)：最初申请的总体目标是确定男性和女性在戒除长期接触自我管理后发生的寻求可卡因和服用可卡因行为逐渐增加或潜伏的条件，并确定潜在的神经生物学特征。在本补充资料中，我们将通过检查延缓这种“孵化效应”的条件来扩展最初的应用。具体地说，在本补充材料中，我们将检验这一假说，即戒酒期间的有氧运动(即车轮跑步)将防止长期接触可卡因自我给药后潜伏的可卡因渴求和相关的神经适应的发生。因此，这一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戒断期间发生的潜在神经生物学变化的影响，像最初的应用一样，我们将重点研究伏隔核和内侧前额叶皮质中多巴胺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。鉴于男性和女性在成瘾形成的时间进程上的已知差异，并基于一项新出现的文献，该文献强调了使用针对性别的干预措施的必要性，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。具体地说，这一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函数。为了达到这一目的，将在线索诱导和压力诱导两种条件下检查可卡因的恢复情况，在延长可卡因自我给药和延长戒断期后，大鼠将有2小时/进入轮子或无法进入。通过Western Blot分析，我们将在大鼠伏隔核和内侧前额叶皮质检测多巴胺(即酪氨酸羟基酶和多巴胺的总水平和磷酸化水平以及cAMP调节的32 kDa的磷蛋白(DARPP-32))、谷氨酸(即NR1和GluR1的总水平和磷酸化水平)以及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、激素和分子化学数据联系起来，以帮助识别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赠款所陈述的最终目标，以确定可以为男性和女性量身定做的潜在干预措施。 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有效性和生物学基础。这项基础科学工作的总体目标是帮助确定运动是否会对可卡因成瘾进行有效的干预，并提供可能指导开发更有效的针对性别的干预措施的信息。

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.