Sex Differences in Vulnerability to Cocaine Addiction

描述(由申请人提供)：了解成瘾初期的性别差异是重要的目标，这一探索性赠款针对的FOA(PAS-07-382)证明了这一点。我们提出了一种新的但基于假设的方法，通过既定的动物程序来检验应激反应和成瘾的性别差异。应激反应与可卡因自我管理的获得有关，可卡因自我管理是一种易上瘾的动物模型。压力反应显示出性别差异，但关于自我管理的报道相互矛盾。母亲护理与后代的压力反应之间的联系被提出；更多的护理与成年人较低的压力反应有关。母体照顾因幼崽性别而异；雄性幼崽比雌性幼崽受到更多的照顾。成年男性表现出比女性更低的压力反应性，这与产妇护理与压力反应性之间的联系一致。我们假设，依赖于性别的产妇护理会影响成人在压力反应和可卡因自我管理方面的性别差异。我们将通过改变幼仔性别组成(LGC；单一性别与混合性别幼崽)来操纵母婴护理来测试这一点，因为单一性别幼崽比混合性别幼崽受到更多的照顾。LGC影响幼鼠的应激反应，以及大鼠和小鼠的幼年和母体行为。我们预测，单性产仔的雄性和雌性成年大鼠比混合性别产仔的后代表现出更低的应激反应能力。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。我们将测量压力暴露后的应激激素水平，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：混血女性和单身女性=混合男性和单身男性。应激反应性和可卡因自身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反应性有关。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的获得，总体上，导致对可卡因自我给药的应激反应的倒U形函数。特定目标2的研究将测试LGC在获得可卡因自我管理方面的影响，同时还将进行一项关于获得食物反应的平行研究。对脚部电击的行为敏感性也将进行调查。数据将提供有关压力反应对成瘾易感性性别差异的影响。公共卫生相关性：这项研究计划的目标是通过动物模型更好地了解性别差异在应激反应和成瘾易感性方面的差异。这项建议中的研究将检验这一假设，即这些性别差异是由于接受的产妇护理中的性别依赖差异，这暗示了成人压力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.