Sex and Stress Mechanisms of Vulnerability to Addiction

性和压力是已知的成瘾易感因素，女性和经历过压力的人 对药物的强化作用更加敏感。压力还会加剧犯罪，从而增加犯罪率 包括生理和心理上的症状。我们假设性、压力和可卡因汇聚在一起 在腹侧被盖区(VTA)内，对多巴胺(DA)有类似的潜在相加效应 发信号。最终，这会导致皮质-边缘-纹状体区域内信号转导的改变。我们的 初步数据显示，应激激素促肾上腺皮质激素释放因子(CRF)在 对可卡因的行为、神经化学和分子反应。我们发现VTA CRF调节 对可卡因的行为反应；它增加CRF向VTA的释放，这种释放使人变得敏感 反复吸食可卡因。VTA CRF拮抗剂也阻止可卡因的自我给药和 可卡因引起的运动敏感化。在这里，我们将描述与以下内容相关的漏洞因素 使用成熟的任务来衡量导致成瘾行为的关键过程-- 获取、狂欢、恢复--确定CRF受体亚型(CRFR1或CRFR2)的作用和 在这些效应中的性行为。我们的目标是建立VTA CRF促进可卡因的机制- 伏隔核额前核内DA信号和分子神经适应的变化 利用体内微透析技术对杏仁皮质和杏仁核下游分子标志物进行免疫印迹分析 (如GluR1、AFosB、CDK5)和蛋白质组学。目标1将确定VTA CRF信号是否更多 与男性相比，女性在获得和复发可卡因自我管理后对可卡因敏感。 我们将研究敏感性如何与发情周期相关，并确定雌激素和 黄体酮对可卡因诱导的VTA CRF反应的影响。线索和压力诱导的复发都将是 调查过了。我们还将使用一种转基因小鼠，其中性腺性行为和染色体性行为 独立检验成瘾成分受性别影响的假设 染色体和性腺激素。我们的初步数据显示，染色体的独立贡献 性行为和性腺性行为在习惯形成和可卡因诱导的运动敏化中的作用。Aim 2将检查 先前的应激经历是否使可卡因诱导的CRF反应和细胞内信号转导敏感 VTA来测试这些影响在女性中更明显的假设。AIM 3将使用CRF受体 以确定CRF受体是否是可卡因自身给药所必需的。采办 男性和女性对可卡因自我给药(线索和应激)和VTA CRF反应的影响和复发 将在先前的慢性压力后进行评估。我们的研究将共同阐明这一关系和潜力 性行为和压力对VTA功能的综合影响。

Sex and stress are known vulnerability factors for addiction, with females and stress-experienced individuals being more sensitive to the reinforcing effects of drugs. Stress also increases recidivism by exacerbating both physiological and psychological symptoms. We hypothesize that sex, stress and cocaine converge within the ventral tegmental area (VTA) having similar, and potentially additive, effects on dopamine (DA) signaling. Ultimately, this leads to altered signal transduction within cortico-limbic-striatal regions. Our preliminary data demonstrate a role for the stress hormone, corticotropin-releasing factor (CRF), in the behavioral, neurochemical and molecular responses to cocaine. We have found that VTA CRF regulates behavioral responses to cocaine; it increases the release of CRF into the VTA and this release sensitizes with repeated cocaine administration. VTA CRF antagonism also blocks cocaine self-administration and cocaine-induced locomotor sensitization. Here we will characterize vulnerability factors associated with addiction using well-established tasks that measure critical processes that contribute to addictive behavior - acquisition, binge, reinstatement - to determine the role for CRF receptor subtypes (CRFR1 or CRFR2)and sex in these effects. Our goal is to establish the mechanism by which VTA CRF contributes to cocaine- induced changes in DA signaling and molecular neuroadaptations within the nucleus accumbens, prefrontal cortex and amygdala using in vivo microdialysis, Western blot analysis of downstream molecular markers (e.g., GluR1, AFosB, CDK5) and proteomics. Aim 1 will determine whether VTA CRF signaling is more sensitive in females compared to males following acquisition of and relapse to cocaine self-administration. We will examine how sensitivity is related to estrus cycle and determine the role of estrogen and progesterone on cocaine-induced VTA CRF responses. Both cue- and stress-induced relapse will be investigated. We will also use a transgenic line of mice in which gonadal sex and chromosomal sex are independent to test the hypothesis that components of addiction are differentially mediated by sex chromosomes and gonadal hormones. Our preliminary data show independent contributions of chromosomal sex and gonadal sex in habit formation and cocaine-induced locomotor sensitization. Aim 2 will examine whether prior stress experience sensitizes cocaine-induced CRF responses and intracellular signaling in the VTA to test the hypothesis that these effects are more pronounced in females. Aim 3 will use CRF receptor deficient mice to establish whether CRF receptors are necessary for cocaine self-administration. Acquisition of and relapse to cocaine self-administration (cue and stress) and VTA CRF responses in males and females will be assessed after prior chronic stress. Together our studies will clarify the relationship and potential converging effects of sex and stress on VTA functioning in vulnerability to addiction.