Sex Difference in Drug Effects: The Prenatal Trajectory

药物作用的性别差异：产前轨迹

• 批准号: 7333536
• 负责人: Emmalee S. Bandstra
• 金额: $ 25.77万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7333536
• 关键词: Address; Adolescent; Affect; Age; Alcohols; Animals; Arousal; Attention; Behavior; Biological; Brain; Child; Clinical; Clinical Research; Cocaine; Condition; Cues; Development; Dose; Drug Exposure; Drug usage; Environment; Environmental Risk Factor; Exhibits; Female; Fetal Cocaine Exposure; Functional Imaging; Household; Imaging Techniques; Individual; Infant; Life; Male Adolescents; Nicotine; Pattern; Perinatal Exposure; Pharmaceutical Preparations; Play; Population; Pre-Clinical Model; Pregnancy; Rate; Rattus; Regulation; Research Personnel; Rewards; Rodent; Role; Sex Characteristics; Staging; Surveys; Target Populations; Testing; Training; Work; base; cognitive function; cohort; day; drug reward; fetal drug exposure; human study; male; neurochemistry; postnatal; pre-clinical; preclinical study; preference; prenatal; prenatal exposure; reproductive; sex; trend

Human studies of children exposed to cocaine prenatally reveal a constellation of effects which include altered attention, affect, arousal regulation and cognitive function. While the effects often differ depending on the sex of the individual, no studies to date have investigated the effects of prenatal cocaine exposure on drug-taking behaviors in female and male offspring. Others have found that postnatal environment plays a role in the manifestation of the effects of many in utero exposures. Since animal studies can differentiate the biological effects of prenatal cocaine exposure from the effects of postnatal environment, we propose to examine the role of postnatal environment in the manifestation of prenatal cocaine effects in male and female offspring. Studies will parallel the clinical projects which are examining drug taking behavior in adolescent male and female subjects exposed to cocaine prenatally. Aim 1: to determine the role of prenatal cocaine exposure in the function of reward circuits in female and male adolescent rats. Prenatally exposed male and female rats will be tested for conditioned place preference (CPP) as adolescents following rearing in an impoverished or a moderately enriched environment. Aim 2: to determine the role of prenatal poly-drug exposure along with cocaine in the development of the reward circuits in male and female rats. The effects of prenatal nicotine, THC and alcohol along with cocaine on CPP for cocaine will be determined in female and male adolescents. Aim 3: to determine the biological basis for the sex differences in reward circuits using functional imaging techniques and neurochemical assessments. Studies will be carried out in subjects treated as in Aims 1 & 2 which show the greatest effects of prenatal cocaine in female and male adolescents undergoing CPP. Following CPP training with a dose of cocaine found to differentiate the prenatal cocaine subjects from the controls, functional imaging studies will be carried out on the test day to visualize the circuits activated by the drug cue. Other rats at 50 days of age will be sacrificed without undergoing CPP and the brains sent to U. Miami for neurochemical assessments. Together these studies will determine the influence of two major confounders in clinical studies (environment and poly- drug use)on the effects of prenatal cocaine exposure emphasizing the differences/similarities of male and female subjects in drug taking behavior using an appropriate preclinical model.

对产前接触可卡因的儿童进行的人体研究揭示了一系列影响，包括改变 注意力、情感、唤醒调节和认知功能。虽然影响往往取决于性别的 在个体中，迄今为止还没有研究调查产前可卡因暴露对吸毒行为的影响， 女性和男性的后代。其他人发现，出生后的环境在这些影响的表现中发挥了作用。 许多子宫内的暴露。由于动物研究可以区分产前接触可卡因的生物效应， 从出生后环境的影响，我们建议检查出生后环境在表现中的作用， 产前可卡因对男女后代的影响。研究将与正在审查的临床项目平行进行。 产前暴露于可卡因的青少年男女受试者的吸毒行为。 目的1：确定产前可卡因暴露在女性和男性奖赏回路功能中的作用 青春期的老鼠将对产前暴露的雄性和雌性大鼠进行条件性位置偏爱（CPP）检测， 在贫困或适度富裕的环境中长大的青少年。 目的2：确定产前多种药物暴露沿着可卡因在奖励发展中的作用 雄性和雌性大鼠的电路。产前尼古丁、四氢大麻酚和酒精沿着可卡因对胎儿CPP的影响 将在男女青少年中测定可卡因含量。 目的3：利用功能成像技术确定奖赏回路性别差异的生物学基础 和神经化学评估。研究将在目标1和目标2所述的受试者中进行，这些研究表明， 产前可卡因对接受CPP的女性和男性青少年的影响最大。经过CPP培训， 可卡因剂量发现，以区分产前可卡因受试者从控制，功能成像研究将是 在测试当天进行，以可视化由药物提示激活的电路。其他50日龄的大鼠将 没有进行CPP而被处死，大脑被送到美国。迈阿密进行神经化学评估。 这些研究将共同确定临床研究中两个主要混杂因素（环境和多聚乙烯）的影响。 强调男性和女性的差异/相似性 使用适当的临床前模型对受试者的服药行为进行评估。