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Sex Differences in Vulnerability to Cocaine Addiction

可卡因成瘾的性别差异

基本信息

批准号：
7813014
负责人：
Therese A Kosten
金额：
$ 25.65万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-30 至 2011-09-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7813014
关键词：
Address Adolescent Adult Affect Aggressive behavior Area Attenuated Back Behavior Behavioral Brain Brain region Caring Cocaine Cocaine Dependence Complex Corticosterone Corticotropin-Releasing Hormone DNA Methylation Data Discipline of Nursing Epigenetic Process Feedback Female Food Funding GPR17 gene Gender Gene Targeting Genes Glucocorticoid Receptor Glucocorticoids Goals Grant Hippocampus (Brain)Hormones Infant Lead Life Link Longevity Maternal Behavior Measures Mediating Mediation Mediator of activation protein Modeling Mus Pattern Pharmaceutical Preparations Play Prefrontal Cortex Procedures Promoter Regions Rattus Recovery Regulation Relative (related person)Research Role Self Administration Sex Characteristics Shapes Shock Stress System Testing United States National Institutes of Health addiction base behavior influence biological adaptation to stress drug reward foot hypothalamic pituitary axis insight male novel novel strategies offspring public health relevance pup response sex social stressor

项目摘要

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.

说明（由申请人提供）：此项拨款是对“NIH 宣布恢复法案资金用于竞争性修订申请的可用性”(NOT-OD-09-058) 的回应。我们提出了一种基于假设的新颖方法，使用既定程序检查压力反应和成瘾方面的性别差异。压力反应与药物自我给药的获得有关，这是一种成瘾脆弱性模型，两者都表现出性别差异。建立了孕产妇护理和后代压力反应之间的联系；更好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介导的。母亲的照顾因幼崽的性别而异；男性比女性受到更多照顾。与孕产妇护理与压力反应性的联系一致，成年男性的压力反应性低于女性。我们假设，性别依赖性孕产妇护理会影响应激反应和可卡因自我给药的性别差异，反映出特定大脑区域（例如 NAc、PFC 和海马体）中特定基因（例如 Gr17、Bdnf）DNA 甲基化的改变。我们将通过改变窝性别构成（LGC；单性别窝与混合性别窝）来操纵孕产妇护理来测试这一点。 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。预计单性别小鼠的雄性和雌性成年大鼠的应激反应性均低于混合性别小鼠的后代。在具体目标 1 中，我们将确认先前的研究表明孕产妇护理对特定性别的影响。我们将测量压力源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。应激反应性与药物自我给药之间的关系很复杂，并且可能是非线性的；低压力反应性和高压力反应性都可能与低反应相关。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，导致可卡因自我给药的应激反应呈倒 U 形函数。具体目标 2 的研究将测试 LGC 对可卡因自我给药和食物反应的影响。具体目标 3 将通过评估与压力反应和药物自我给药相关的大脑区域中目标基因的 DNA 甲基化模式来解决这些性别差异的表观遗传贡献。数据将揭示孕产妇护理的作用以及导致压力反应和成瘾方面性别差异的潜在表观遗传机制。公共卫生相关性：这项研究的目的是更好地了解压力反应性和成瘾脆弱性方面的性别差异。这项竞争性修订的研究将检验以下假设：这些性别差异是由于接受的产妇护理方面的性别依赖性差异造成的，并反映了选定大脑区域中目标基因的表观遗传效应。