Drug Abuse: Sex differences in developmental and environmental influences

描述（由申请人提供）：本实验旨在探讨产前压力和女性身份这两个药物滥用危险因素之间的相互作用。据推测，产前压力改变了男性和女性对新情况的不同反应的神经系统，但对两性来说，结果是对可卡因的反应增强，从而增加了吸毒行为的脆弱性。产前压力使发育中的生物体暴露于糖皮质激素水平增加的时期，这段时间是关键的生长时期，因此对神经系统的发育有深远的影响，因此对成年后代的生理和行为也有深远的影响。产前压力的一些后果包括压力轴功能障碍、学习障碍、抑郁、精神病理和潜在的药物滥用倾向的增加。在许多药物滥用方面存在性别差异，尽管有更多的男性有药物滥用障碍，但女性对可卡因上瘾的速度要比男性快。女性开始使用可卡因的年龄更早，接受治疗的年龄更早，并且在摄入可卡因时比男性产生更严重的可卡因依赖。在大鼠中，雌性大鼠对可卡因表现出增强的行为敏感性，它们以更低的剂量更快地获得可卡因自我给药，并且雌性大鼠比雄性大鼠表现出更大的服用可卡因的动机。在初步实验的结果中，我们发现雄性大鼠的产前应激增强了反复使用可卡因后的行为敏化，并获得了可卡因的自我管理。在雌性中，初步实验结果表明，产前应激增强了对新奇事物的运动反应、对可卡因的急性反应、对可卡因的行为敏感，以及在发情周期的某些日子里吸食可卡因的量。因此，女性在产前压力后也有增加的风险。提出的实验将通过改变应激系统相关基因表达和改变伏隔核和纹状体多巴胺功能来验证产前应激增加男性和女性对可卡因和可卡因自我给药行为反应的脆弱性的假设。据推测，产前压力对男性和女性的影响机制是不同的，但对两性的影响都是对可卡因的反应增强，从而增加了吸毒行为的脆弱性。重要的是，许多产前压力的影响可以通过交叉培养到无压力的水坝来逆转。实验还将探讨母体行为在多大程度上改善产前应激对应激系统相关基因表达的影响，改变伏隔核和纹状体多巴胺功能以及对药物服用行为的影响。公共卫生相关性：为什么有些人开始滥用药物？提出的实验将调查男性和女性的大脑在产前压力可能导致成瘾的后果中出现了什么问题，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措施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.