Sex Differences in Vulnerability to Cocaine Addiction

描述(由申请人提供)：这项拨款是对“美国国立卫生研究院宣布恢复法资金可用于竞争性修订申请”(NOT-OD-09-058)的回应。我们提出了一种新的但基于假设的方法，使用既定的程序来检查压力反应和成瘾的性别差异。应激反应与药物自我管理的获得有关，这是一种成瘾易感性模型，并且两者都表现出性别差异。产妇护理与子女的压力反应之间的联系已经确立；更多的护理与成人较低的压力反应有关。此外，这些效应是通过表观遗传机制来调节的。母体护理因幼崽性别不同而不同；雄性比雌性受到更多的照顾。与母亲护理与压力反应的联系一致，成年男性的压力反应比女性低。我们假设，性别依赖的产妇护理影响应激反应和可卡因自我给药的性别差异，这些差异反映了特定大脑区域(如NAC、PFC和海马体)特定基因(如Gr17、BDNF)DNA甲基化的改变。我们将通过改变产仔性别组成(LGC；单一性别产仔与混合性别产仔)来操纵母婴护理来测试这一点。LGC影响幼鼠的应激反应，以及大鼠和小鼠的幼年和母体行为。据预测，单性产仔的雄性和雌性成年大鼠的应激反应都比混合性别产仔的后代要低。在具体目标1中，我们将确认先前关于产妇护理对性别的影响的研究。我们将测量应激源的应激激素水平，并评估糖皮质激素的反馈敏感性。我们预测LGC对应激反应的影响如下：混合女性和单身女性=混合男性和单身男性。应激反应性和药物自我给药之间的关系是复杂的，可能是非线性的；低应激反应性和高应激反应性都可能与低应激反应有关。因此，我们预测LGC将减弱混合女性和单身男性的可卡因自我给药，导致应激反应对可卡因自我给药的倒U形函数。特定目标2的研究将测试LGC对可卡因获得、自我给药和食物反应的影响。具体目标3将通过评估与应激反应和药物自我给药相关的脑区靶基因的DNA甲基化模式，解决表观遗传学对这些性别差异的影响。数据将提供有关产妇护理的作用和潜在的表观遗传机制的信息，这些机制有助于在压力反应和成瘾方面产生性别差异。 公共卫生相关性：这项研究的目标是更好地了解性别在压力反应和成瘾易感性方面的差异。这一竞争性修订中的研究将检验这样一种假设，即这些性别差异是由于接受的产妇护理的性别差异所致，并反映了选定大脑区域中目标基因的表观遗传效应。

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.