Sex Differences in Vulnerability to Cocaine Addiction

描述（由申请人提供）：该资助响应“NIH宣布竞争性修订申请的恢复法案基金可用性”（NOT-OD-09-058）。我们提出了一种新颖的基于假设的方法，使用既定的程序来检查压力反应性和成瘾的性别差异。应激反应与药物自我管理的获得有关，这是成瘾脆弱性的一种模式，两者都存在性别差异。建立了产妇护理与后代的应激反应之间的联系；更多的照顾与成年人较低的压力反应有关。此外，这些影响是通过表观遗传机制介导的。母性照顾因幼崽性别而异；男性比女性得到更多的照顾。与母性照顾与应激反应的关系一致，成年男性的应激反应低于女性。我们假设性别依赖性的母性护理影响应激反应和可卡因自我给药的性别差异，反映了特定大脑区域（如NAc、PFC和海马）中特定基因（如Gr17、Bdnf）的DNA甲基化改变。我们将通过改变产仔性别组成（LGC；单性别产仔vs混合性别产仔）来操纵产妇护理来验证这一点。LGC影响幼鼠的应激反应以及大鼠和小鼠的幼鼠和母鼠行为。雌雄同体的成年大鼠都比雌雄同体的后代表现出更低的应激反应。在具体目标1中，我们将证实先前的研究表明产妇护理的性别特异性影响。我们将测量应激激素水平对应激源和评估糖皮质激素反馈敏感性。我们预测LGC对应激反应的影响如下：混合雌性>单一雌性>=混合雄性>单一雄性。应激反应与自我给药之间的关系是复杂的，可能是非线性的；低压力反应和高压力反应都可能与低反应有关。因此，我们预测LGC会减弱混合女性和单一男性的可卡因自我给药，导致对可卡因自我给药的应激反应呈倒u型函数。特定目标2的研究将测试LGC对可卡因自我给药和食物反应的获得的影响。特异性目标3将通过评估与应激反应和药物自我给药相关的大脑区域中靶向基因的DNA甲基化模式来解决这些性别差异的表观遗传学贡献。数据将告知产妇护理的作用和潜在的表观遗传机制，有助于压力反应和成瘾的性别差异。

DESCRIPTION (provided by applicant): This grant responds to "NIH Announces the Availability of Recovery Act Funds for Competitive Revision Applications" (NOT-OD-09-058). We propose a novel yet hypothesis-based approach to examine sex differences in stress responsivity and addiction using established procedures. Stress responsivity relates to acquisition of drug self-administration, a model of addiction vulnerability, and both shows sex differences. Links between maternal care and stress responsivity of offspring are established; greater care relates to lower stress responsivity in adults. Further, these effects are mediated via epigenetic mechanisms. Maternal care differs by pup sex; males receive more care than females. Consistent with the link of maternal care with stress responsivity, adult males show lower stress responsivity than females. We hypothesize that sex-dependent maternal care influences sex differences in stress responsivity and cocaine self-administration reflecting altered DNA methylation of specific genes (e.g., Gr17, Bdnf) in select brain areas (e.g., NAc, PFC, and hippocampus). We will test this by manipulating maternal care via altering litter gender composition (LGC; single- vs mixed-sex litters). LGC influences stress responsivity in infant mice and juvenile and maternal behaviors in rats and mice. Both male and female adult rats of single-sex litters are predicted to show lower stress responsivity than offspring of mixed-sex litters. In Specific Aim 1, we will confirm prior studies demonstrating sex-specific effects of maternal care. We will measure stress hormone levels to stressors and assess glucocorticoid feedback sensitivity. We predict the following effects of LGC on stress responses: mixed females>single females >=mixed males>single males. The relationship between stress responsivity and drug self-administration is complex and may be non-linear; both low and high stress responsivity may associate with low responding. Thus, we predict LGC will attenuate cocaine self-administration in mixed females and single males resulting in an inverted U-shaped function of stress responsivity to cocaine self-administration. Studies in Specific Aim 2 will test effects of LGC on acquisition of cocaine self-administration and food responding. Specific Aim 3 will address epigenetic contributions to these sex differences by assessing DNA methylation patterns of targeted genes in brain regions associated with stress responsivity and drug self-administration. Data will inform on the role of maternal care and underlying epigenetic mechanisms that contribute to sex differences in stress responsivity and addiction. PUBLIC HEALTH RELEVANCE: The goal of this research is to achieve a better understanding of sex differences in stress responsivity and vulnerability to addiction. Studies in this competitive revision will test the hypothesis that these sex differences are due to sex-dependent differences in maternal care received and reflect epigenetic effects of targeted genes in select brain regions.