Sex Differences in Vulnerability to Cocaine Addiction

描述（由申请人提供）：了解成瘾开始过程中的性别差异是重要的目标，这一点在FOA （PAS-07-382）中得到了证明。我们提出了一种新颖的基于假设的方法，使用既定的动物程序来检查压力反应性和成瘾的性别差异。应激反应与获得可卡因自我管理有关，这是一种易上瘾的动物模型。压力反应表现出性别差异，但关于自我管理的报告却相互矛盾。提出了产妇护理与后代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。母性照顾因幼崽性别而异；雄性幼崽比雌性幼崽得到更多的照顾。成年男性的应激反应低于女性，这与母性护理与应激反应的联系是一致的。我们假设性别依赖的母性护理影响成人应激反应和可卡因自我给药的性别差异。我们将通过改变产仔性别组成（LGC；单性别与混合性别产仔）来操纵母性照顾来验证这一点，因为单性别产仔比混合性别产仔得到更多的照顾。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。我们预测单性窝的雄性和雌性成年大鼠都比混合性别窝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。我们将测量应激暴露后的应激激素水平，并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。应激反应与可卡因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对可卡因自我给药的获得性，总体而言，导致对可卡因自我给药的应激反应呈倒u型函数。具体目标2中的研究将测试LGC对可卡因自我给药获得的影响，并进行平行的食物反应获得研究。对足部电击的行为敏感性也将进行调查。数据将告知压力反应对成瘾脆弱性性别差异的贡献。公共卫生相关性：本研究项目的目的是利用动物模型更好地了解压力反应性和成瘾易感性的性别差异。本研究将验证这一假设，即这些性别差异是由于母亲照顾的性别依赖差异引起的，这暗示了成人应激和药物反应的性别差异的表观遗传起源。

DESCRIPTION (provided by applicant): Understanding sex differences in the initiation to addiction are important goals as evidenced by the FOA (PAS-07-382) to which this exploratory grant is addressed. We propose a novel yet hypothesis-based approach to examine sex differences in stress responsivity and addiction using established animal procedures. Stress responsivity relates to acquisition of cocaine self-administration, an animal model of vulnerability to addiction. Stress responsivity shows sex differences but reports on self-administration are conflicting. Links between maternal care and stress responsivity of offspring are proposed; greater care relates to lower stress responsivity of adults. Maternal care differs by pup sex; male pups receive more care than female pups. Adult males show lower stress responsivity than females consistent with the link of maternal care with stress responsivity. We hypothesize that sex-dependent maternal care influences sex differences in stress responsivity and cocaine self-administration in the adult. We will test this by manipulating maternal care via altering litter gender composition (LGC; single- vs mixed-sex litters) because pups of single-sex litters receive more care than pups of mixed-sex litters. LGC influences stress responsivity in infant mice and juvenile and maternal behaviors in rats and mice. We predict both male and female adult rats of single-sex litters will 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 after stress exposures and assess glucocorticoid feedback sensitivity. We predict the following effects of LGC on stress responsivity: mixed females>single females >=mixed males>single males. The relationship between stress responsivity and cocaine 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 acquisition of cocaine self-administration in mixed females and single males and, overall, result in an inverted U-shaped function of stress responsivity to cocaine self-administration. Studies in Specific Aim 2 will test the effects of LGC on acquisition of cocaine self-administration with a parallel study on acquisition of food responding. Behavioral sensitivity to foot shock will also be investigated. Data will inform on contributions of stress responsivity to sex differences in vulnerability to addiction. PUBLIC HEALTH RELEVANCE: The goal of this research program is to achieve a better understanding of sex differences in stress responsivity and vulnerability to addiction using animal models. Studies in this proposal will test the hypothesis that these sex differences are due to sex-dependent differences in maternal care received suggestive of epigenetic origins of the sex differences in stress and drug responses in the adult.