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

描述（由申请人提供）：阐明酒精对青少年大脑的影响是至关重要的，不仅要了解成瘾过程的本质，而且要防止从偶然饮酒发展到依赖。这项提议的总体目标是验证这样一种假设，即青少年的大脑特别容易受到乙醇引起的生理变化的影响，而这些酒精在青春期引起的扰动会持续到成年，使动物更容易受到酒精成瘾的影响。具体来说，我们认为青少年时期的乙醇暴露会改变关键的神经回路，而这些变化会持续到成年，导致这一通路正常功能的改变，这可能是导致“酒精暴露”的大脑比“酒精幼稚”的大脑更容易使用乙醇的原因。本实验旨在确定雄性和雌性大鼠在青春期[产后30-50天]或成年期（60-80天）长期暴露于实验者给予的乙醇（或生理盐水）的性别差异。在乙醇（或生理盐水）暴露后，将对青春期暴露的大鼠和成年暴露的大鼠进行成年后测试（分别为PND 74或PND 104），以了解乙醇预暴露对通过自愿摄入甜味乙醇而消耗乙醇的影响（具体目标1）。对于一项神经化学测量，酒精诱导的伏隔核多巴胺能反应，可能在酒精使用到酒精依赖的过程中受到影响，将通过体内微透析测量实验者给予的乙醇（0.75、1.75 g/kg/ip乙醇）或生理盐水的反应（Specific Aim 2）。在所有拟议的实验中，将检查血液和脑乙醇浓度，以确定乙醇代谢中可能的性别和预处理差异。此外，将评估所有成年女性的发情周期，以调查青春期或成年期慢性乙醇暴露对长期行为和神经化学后果的发情周期变化的影响。这些研究的结果将清楚地描述与成年期相比，青春期长期接触乙醇对成年后大脑和行为的持久影响。关于乙醇消费模式的改变和使动物对乙醇成瘾敏感的大脑神经化学过程的信息对于理解成瘾过程以及如何预防或治疗至关重要。

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.