Sex Differences in Vulnerability to Cocaine Addiction

描述（由申请人提供）：了解成瘾开始的性别差异是重要的目标，这一点由FOA（PAS-07-382）证明，该探索性补助金是针对。我们提出了一种新的假设为基础的方法来研究性别差异的压力反应和成瘾使用既定的动物程序。应激反应与可卡因自我给药的获得有关，这是一种易成瘾的动物模型。压力反应显示性别差异，但自我管理的报告是相互矛盾的。产妇护理和压力反应的后代之间的联系，提出了更大的照顾涉及到较低的压力反应的成年人。母亲的照顾因幼崽的性别而异;雄性幼崽比雌性幼崽得到更多的照顾。成年男性表现出较低的压力反应性比女性一致的孕产妇护理与压力反应性的联系。我们假设，性别依赖的孕产妇保健影响压力反应和可卡因自我管理的性别差异在成年人。我们将通过改变胎仔性别组成（LGC;单性别与混合性别胎仔）来操纵母性护理来测试这一点，因为单性别胎仔的幼崽比混合性别胎仔的幼崽得到更多的护理。LGC影响幼年小鼠的应激反应以及大鼠和小鼠的幼年和母体行为。我们预测雄性和雌性成年大鼠的单一性别的窝将显示较低的应激反应比后代的混合性别的窝。在具体目标1中，我们将确认先前的研究，这些研究证明了孕产妇护理的性别特异性影响。我们将测量压力暴露后的压力激素水平，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：混合女性>单身女性>=混合男性>单身男性。应激反应和可卡因自我给药之间的关系是复杂的，可能是非线性的;低和高应激反应可能与低反应。因此，我们预测LGC将减弱混合女性和单身男性可卡因自我管理的收购，总体而言，导致可卡因自我管理的压力反应的倒U形函数。特定目标2中的研究将测试LGC对可卡因自我给药获得的影响，并对食物反应获得进行平行研究。还将研究对足部电击的行为敏感性。数据将告知的贡献，压力反应性的性别差异的脆弱性成瘾。公共卫生相关性：这项研究计划的目标是更好地了解性别差异的压力反应和脆弱性成瘾使用动物模型。本提案中的研究将检验这一假设，即这些性别差异是由于所接受的孕产妇护理的性别依赖性差异，这暗示了成年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.