Sex Differences in Adolescent Vulnerability to Morphine

描述（由申请人提供）： 青少年发育阶段是一个特别脆弱的时期，在此期间，尝试毒品达到一生中的高峰，往往开始从娱乐性使用到对阿片类药物等药物的不可控制的依赖的问题轨迹。虽然美国的大多数药物滥用者是男性，但越来越多的女性是药物依赖者，女性滥用阿片类处方止痛药的可能性是男性的4-5倍。然而，直到最近，青少年和女性受试者才在使用动物模型的研究中进行了测试，以探索药物寻求行为。因此，无法解释在易受药物滥用影响方面与年龄和性别有关的差异。此外，潜在的风险因素，区分青少年谁启动的药物依赖轨迹与那些谁没有保持未探索。导致青少年吸毒的因素可能包括先前的压力或创伤;不良的新生儿环境显然会增加成年后的吸毒成瘾。然而，新生儿创伤对青少年男性和女性阿片类药物自我管理的具体影响尚不清楚。本申请中提出的实验将使用行为技术来测试这些假设：（1）青少年药物脆弱性延伸到吗啡的强化作用;（2）通过后爪注射炎症剂导致的新生儿损伤导致雄性和雌性青春期大鼠吗啡自我给药增加;以及（3）这些作用在雌性中加剧。这些行为的影响被假设为介导的发育变化和性二态性的阿片类神经回路在大脑中的解剖和功能组织，我们将在未来的实验中使用细胞和分子技术进行测试。这些研究将共同提供一个生物学基础，即不利的新生儿环境增强了男女青少年对药物滥用的脆弱性。

DESCRIPTION (provided by applicant): The adolescent phase of development is a particularly vulnerable period during which experimentation with drugs reaches a lifetime high, often initiating a problematic trajectory from recreational use to uncontrollable dependence on drugs such as opiates. Although the majority of drug abusers in the U.S. are male, an increasing number of women are drug dependent, and females are 4-5 times more likely than males to abuse opioidergic prescription pain killers. Yet only recently have adolescent and female subjects been tested in research using animal models to explore drug-seeking behavior. Therefore, age- and sex-related differences in vulnerability to drug abuse are unexplained. Moreover, potential risk factors which differentiate between adolescents who initiate the drug dependence trajectory vs. those who do not remain unexplored. Factors contributing to adolescent drug intake are likelly to include prior stress or trauma; adverse neonatal environments clearly increase drug addiction in adulthood. However, the specific impact of neonatal trauma on opiate self-administration in adolescent males and females is not known. Experiments proposed in this application will use behavioral techniques to test these hypotheses: (1) adolescent drug vulnerabilities extend to the reinforcing effects of morphine; (2) neonatal injury via hindpaw injection of an inflammatory agent results in elevated morphine self-administration in both male and female adolescent rats; and (3) that these effects are exacerbated in females. These behavioral effects are hypothesized to be mediated by developmental changes and sexual dimorphisms in the anatomical and functional organization of opioidergic circuits in the brain, which we will test in future experiments using cellular and molecular techniques. Together these studies will provide a biological basis whereby an adverse neonatal environment potentiates adolescent vulnerabilities to drug abuse in males and females.