Sex and Stress Mechanisms of Vulnerability to Addiction

性和压力是成瘾的已知脆弱因素，女性和有压力经历的人 对药物的强化作用更加敏感。压力也会加剧 生理和心理症状。我们假设性、压力和可卡因 在腹侧被盖区（VTA）内，对多巴胺（DA）具有类似的和潜在的累加作用， 发信号。最终，这导致皮质-边缘-纹状体区域内的信号转导改变。我们 初步数据表明，应激激素促肾上腺皮质激素释放因子（CRF）在 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;它增加了CRF释放到VTA中，这种释放使 反复服用可卡因VTA CRF拮抗作用还阻断可卡因自我给药， 可卡因引起的运动敏感在这里，我们将描述与以下方面相关的脆弱性因素： 成瘾使用完善的任务来衡量导致成瘾行为的关键过程- 获得，狂欢，恢复-确定CRF受体亚型（CRFR 1或CRFR 2）的作用， 性在这些影响中。我们的目标是建立VTA CRF有助于可卡因的机制- 诱导多巴胺信号传导和分子神经适应性的变化，在延髓核，前额叶 皮质和杏仁核使用在体微透析，下游分子标记的Western印迹分析 (e.g., GluR 1、AFosB、CDK 5）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，女性在获得可卡因自我给药和可卡因自我给药复发后敏感。 我们将研究敏感性与发情周期的关系，并确定雌激素的作用， 孕酮对可卡因诱导的VTA CRF反应的影响。暗示和压力诱导的复发都将是 研究了我们还将使用一种转基因小鼠品系，其中性腺性别和染色体性别是 独立检验成瘾成分由性别差异介导的假设 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 习惯形成和可卡因诱导的运动敏化中的性别和性腺性别。目标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来检验这些影响在女性中更明显的假设。目标3将使用CRF受体 缺陷小鼠，以确定CRF受体是否是可卡因自我给药所必需的。采集 男性和女性可卡因自我给药（提示和压力）和VTA CRF反应的复发 将在之前的慢性压力后进行评估。我们的研究将共同阐明 性和压力对腹侧被盖区成瘾易感性的影响。

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.