Sex Differences in Adolescent Vulnerability to Morphine

描述(由申请人提供)： 青少年发展阶段是一个特别脆弱的时期，在此期间，毒品试验达到一生中的最高水平，经常引发从娱乐使用到对阿片剂等药物的失控依赖的问题轨迹。尽管美国大多数吸毒者是男性，但越来越多的女性依赖药物，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通过动物模型进行了研究，以探索寻求毒品的行为。因此，与年龄和性别相关的药物滥用易感性差异是无法解释的。此外，潜在的危险因素区分了那些开始药物依赖轨迹的青少年和那些不是未被发现的青少年。导致青少年吸毒的因素很可能包括先前的压力或创伤；不利的新生儿环境显然会增加成年后的吸毒成瘾。然而，新生儿创伤对青春期男性和女性阿片类药物自我给药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检验这些假设：(1)青少年的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造成的新生儿损伤导致雄性和雌性青春期大鼠的吗啡自我管理水平提高；以及(3)这些影响在雌性大鼠中加剧。这些行为效应被认为是由大脑阿片能回路的解剖和功能组织中的发育变化和性别二型性所介导的，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使青少年在男性和女性中更容易受到药物滥用的影响。

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.