Effects of Chronic ethanol exposure in male and female adolescents on behavior an

说明（由申请人提供）：阐明酒精对青少年大脑的影响至关重要，不仅要了解成瘾过程的性质，而且要防止从偶然使用酒精到依赖的进展。本提案的总体目标是检验以下假设：青少年大脑对乙醇引起的生理变化特别敏感，并且这些乙醇引起的青春期扰动持续到成年期，使动物更容易受到其成瘾效应的影响。具体来说，我们建议，乙醇暴露在青春期改变关键的神经元回路，这些变化持续到成年期，随之而来的变化，在正常功能的这条途径，可能是负责的易感性的“乙醇暴露”的大脑乙醇使用相比，“乙醇天真”的大脑。拟定实验旨在确定雄性和雌性大鼠在青春期[出生后（PND）30-50天]或成年期（PND 60-80天）长期暴露于实验者给予的乙醇（或生理盐水）的长期影响的性别差异。乙醇（或生理盐水）暴露后，将作为成年大鼠（分别为PND 74或PND 104）检测酒精暴露和成年暴露大鼠，以确定酒精预暴露对自愿摄入加糖乙醇的乙醇消耗量的影响（具体目标1）。对于神经化学测量，将使用体内微透析（特定目标2）测量乙醇诱导的隔隔核多巴胺能反应（可能受影响并依次参与从酒精使用到酒精依赖的进展）对实验者给予的乙醇（0.75，1.75 g/kg/ip乙醇）或盐水的反应。将在所有拟定实验中检查血液和脑乙醇浓度，以确定乙醇代谢中可能的性别和给药前差异。此外，将在成年期对所有雌性动物的发情周期进行评价，以研究发情周期变化对青春期或成年期长期乙醇暴露的长期行为和神经化学后果的影响。这些研究的结果将清楚地描述青春期长期接触乙醇与成年期相比对随后的成年大脑和行为的持久影响。乙醇消费模式和大脑神经化学过程的改变，使动物易受乙醇成瘾的信息是至关重要的成瘾过程，以及如何预防或治疗。 公共卫生相关性：这些研究将检查酒精对成年男性和女性大脑的长期影响，以及青春期或成年期接触酒精后的行为。

DESCRIPTION (provided by applicant): Elucidating the impact of alcohol on the adolescent brain is of paramount importance not only to understand the nature of the addictive process but also to prevent the progression from casual alcohol use to dependency. The overall goal of this proposal is to test the hypothesis that the adolescent brain is uniquely susceptible to physiological changes induced by ethanol and that these ethanol-induced perturbations during adolescence persist into adulthood rendering the animals more vulnerable to its addicting effects. Specifically, we propose that ethanol exposure during adolescence alters key neuronal circuitry and that these changes persist into adulthood with consequent changes in the normal functions of this pathway that may be responsible for the predisposition of the "ethanol-exposed" brain to ethanol use as compared to the "ethanol-naive" brain. The proposed experiments are designed to determine sex differences in the long-term effects of chronic exposure to experimenter administered ethanol (or saline) during adolescence [postnatal day (PND) 30-50] or adulthood (PND 60-80) in male and female rats. Following ethanol (or saline) exposure, adolescent-exposed and adult- exposed rats will be tested as adults (PND 74 or PND 104, respectively) for the effects of ethanol preexposure on ethanol consumption via voluntary sweetened ethanol intake (Specific Aim 1). For a neurochemical measure, ethanol-induced dopaminergic responses of the nucleus accumbens septi, likely to be affected and involved sequentially in the progression from alcohol use to alcohol dependency, will be measured in response to experimenter-administered ethanol (0.75, 1.75 g/kg/ip ethanol) or saline using in vivo microdialysis (Specific Aim 2). Blood and brain ethanol concentrations will be examined in all proposed experiments to determine possible sex and pretreatment differences in the metabolism of ethanol. Additionally, estrous cycling will be evaluated in all females during adulthood to investigate the effects of changes in the estrous cycle on long term behavioral and neurochemical consequences of chronic ethanol exposure during adolescence or adulthood. Results from these studies will clearly delineate the lasting impact of chronic exposure to ethanol during adolescence as compared to adulthood on the subsequent adult brain and behavior. Information on the alteration of ethanol consumption patterns and neurochemical processes of the brain that render animals susceptible to ethanol addiction is critically important for understanding the addictive process and how it may be prevented or treated. PUBLIC HEALTH RELEVANCE: These studies will examine the long term effects of ethanol on the adult male and female brain and behavior following ethanol exposure during adolescence or adulthood.