Drug Abuse: Sex differences in developmental and environmental influences

描述（由申请人提供）：拟进行实验以研究药物滥用的两个风险因素之间的相互作用：产前压力和女性。据推测，产前压力改变了神经系统，对新的情况下，男性与女性的差异，但对两性的后果是一个增强的反应可卡因，增加了脆弱性吸毒行为。产前应激使发育中的生物体暴露于增加的糖皮质激素水平，在此期间发生关键生长，因此对神经系统的发育以及成年后代的生理和行为产生深远的影响。产前压力的一些后果包括压力轴功能障碍、学习障碍、抑郁症、精神病理学和潜在的药物滥用倾向增加。许多滥用药物的滥用情况存在性别差异，尽管患有药物滥用障碍的男子较多，但妇女对可卡因成瘾的速度比男子快。妇女开始使用可卡因的年龄较早，接受治疗的年龄较早，在摄入可卡因时比男子更严重地依赖可卡因。在大鼠中，雌性大鼠表现出对可卡因的增强的行为敏感性，它们获得可卡因自我管理更迅速，剂量更低，雌性大鼠表现出更大的动机比雄性大鼠服用可卡因。在初步实验的结果中，我们发现在雄性大鼠中，产前应激增强了重复可卡因后的行为敏感性，以及可卡因自我给药的获得。在女性中，试点实验的结果表明，产前压力增强了运动反应的新奇，急性反应可卡因，可卡因的行为敏感化，并在某些天的动情周期的可卡因量。因此，在产前压力后，女性的风险也会增加。提出的实验将检验这样的假设：产前压力通过改变压力系统相关基因表达以及伏隔核和纹状体中多巴胺功能的变化，增加男性和女性对可卡因和可卡因自我给药的行为反应的脆弱性。假设产前压力的影响的机制是不同的男性与女性，但对两性的后果是一个增强的反应，可卡因，增加吸毒行为的脆弱性。重要的是，产前压力的许多影响可以通过交叉寄养到无压力的母鼠来逆转。实验还将研究母体行为在多大程度上可以改善产前应激对应激系统相关基因表达的影响，改变中脑核和纹状体中多巴胺的功能以及对吸毒行为的影响。公共卫生相关性：为什么有些人开始滥用药物？拟议中的实验将调查男性和女性的大脑中出现了什么问题，作为可能导致成瘾的产前压力的结果，以及是否有可能通过改变母亲的行为来补偿这些影响。这些实验的结果将对使用非药物干预治疗和预防药物滥用产生影响。

DESCRIPTION (provided by applicant): Experiments are proposed to investigate the interaction between two risk factors for drug abuse: prenatal stress and being female. It is hypothesized that prenatal stress alters the neural systems that respond to novel situations differentially in males vs. females, but the consequences for both sexes is an enhanced response to cocaine which increases vulnerability for drug taking behavior. Prenatal stress exposes the developing organism to increased levels of glucocorticoids at a time during which critical growth is taking place so there are profound effects on the development of the nervous system and as a consequence the physiology and behavior of the adult offspring. Some of the consequences of prenatal stress include dysfunction of the stress axis, learning disabilities, depression, psychopathology and potentially an increased propensity to develop drug abuse. There are sex differences in drug abuse for many drugs of abuse, and even though there are more men with substance abuse disorders, the onset of addiction to cocaine is more rapid in women than in men. Women begin using cocaine at an earlier age, enter treatment at earlier ages and have developed more severe cocaine dependence at intake than men. In rats, female rats exhibit an enhanced behavioral sensitization to cocaine, they acquire cocaine self-administration more rapidly and at lower doses, and females exhibit greater motivation to take cocaine than do male rats. In results from pilot experiments we find in male rats that prenatal stress enhances behavioral sensitization following repeated cocaine, and acquisition of cocaine self-administration. In females, results of pilot experiments indicate that prenatal stress enhances the locomotor response to novelty, the acute response to cocaine, behavioral sensitization to cocaine, and the amount of cocaine taken on certain days of the estrous cycle. Thus, there is also increased risk for females after prenatal stress. Experiments proposed will test the hypothesis that prenatal stress increases vulnerability of males and females for the behavioral response to cocaine and cocaine self-administration via altered stress system-related gene expression and changes in dopamine function in the nucleus accumbens and striatum. The mechanisms mediating the effects of prenatal stress are hypothesized to be different for males vs. females, but the consequences for both sexes is an enhanced response to cocaine which increases vulnerability for drug taking behavior. Importantly, many of the effects of prenatal stress can be reversed by cross-fostering to non- stressed dams. Experiments will also investigate the extent that maternal behavior can ameliorate the effects of prenatal stress on stress system-related gene expression, change dopamine function in the nucleus accumbens and striatum and on drug taking behavior. PUBLIC HEALTH RELEVANCE: Why do some individuals start taking drugs of abuse? Experiments proposed will investigate what goes wrong in the brains of males and females as consequence of prenatal stress that may lead to addiction, and whether it is possible to compensate for these effects by changes in maternal behavior. Results from these experiments will have implications for treatment and prevention of drug abuse using non-pharmacological interventions.