Drug Abuse: Sex differences in developmental and environmental influences

描述(由申请人提供)：建议进行实验，以调查药物滥用的两个风险因素之间的相互作用：产前应激和女性。据假设，产前应激改变了男性和女性对新情况的不同反应的神经系统，但对男性和女性的后果是对可卡因的反应增强，这增加了吸食毒品行为的易感性。产前应激使发育中的有机体暴露在糖皮质激素水平升高的环境中，而此时正是发育的关键时期，因此对神经系统的发育以及成年后代的生理和行为都会产生深远的影响。产前应激的一些后果包括应激轴功能障碍、学习障碍、抑郁、精神病理和潜在的药物滥用倾向增加。许多滥用药物的药物滥用存在性别差异，尽管患有药物滥用障碍的男性更多，但女性对可卡因上瘾的速度比男性更快。女性在更早的年龄就开始使用可卡因，在更早的年龄接受治疗，并且在摄入可卡因时产生了比男性更严重的可卡因依赖。在大鼠中，雌性大鼠表现出对可卡因的行为敏感度增强，它们获得可卡因自我管理的速度更快，剂量更低，雌性大鼠比雄性大鼠表现出更大的动机服用可卡因。在先导实验的结果中，我们发现在雄性大鼠中，产前应激增强了重复使用可卡因后的行为敏感化，并获得了可卡因自我给药。在女性中，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化，以及在发情周期的某些日子里服用的可卡因的量。因此，女性在产前应激后的风险也会增加。提出的实验将检验这一假设，即产前应激通过改变应激系统相关基因的表达和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管理的行为反应的脆弱性。据推测，产前应激影响的机制对男性和女性是不同的，但对男性和女性的后果是对可卡因的增强反应，这增加了吸毒行为的易感性。重要的是，孕期应激的许多影响可以通过交叉培育到非应激的水坝来逆转。实验还将调查母亲的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，改变伏隔核和纹状体的多巴胺功能，以及对吸毒行为的影响。公共卫生相关性：为什么一些人开始服用滥用药物？拟议中的实验将调查可能导致成瘾的产前压力导致男性和女性大脑出现什么问题，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.