Ontogeny of Response to Ethanol After Prenatal Ethanol

描述（由申请人提供）：在青春期或青春期前使用乙醇明显预示着以后的生活中酒精滥用。青少年使用乙醇是因为更早接触乙醇吗？人类和大鼠实验的流行病学证据表明，在青春期接受乙醇是由产前暴露于乙醇增强。本研究验证了一个假设，即妊娠后期少量适度、无害剂量的乙醇会改变以后对乙醇的反应，包括从出生到青春期的乙醇接受和强化，以及青春期乙醇的激活效应。这一假设得到了初步研究的支持，这些研究表明，产前乙醇暴露不仅增加了后来的乙醇接受度，而且增加了增强食欲的乙醇剂量的范围。在每个拟议的实验中，将评估在妊娠17-20天每天给予0、1或2 g/kg乙醇或对照治疗的动物出生后对乙醇的反应。具体目标1是测试乙醇摄入和乙醇强化出生后不久，在三种不同的强化范式。具体目标2是测试的效果。产前乙醇对乙醇接受和乙醇强化在青春期和在出生和青春期之间的中间点（出生后第15天，P15）。具体目标3是测试产前乙醇暴露的后果，以确定乙醇在青春期的激活效应，乙醇诱导的社会促进。鉴于内源性阿片系统在乙醇摄入、乙醇强化和青少年社会行为中的明显作用，特异性目的4是测试产前乙醇对β -内啡肽基因表达、β -内啡肽脑水平和？-阿片受体结合与乙醇摄入、乙醇强化和乙醇诱导的社会行为相关。这些测试将在出生后不久，在P15或青春期进行。目的是阐明适度暴露于产前乙醇的风险的个体发生，并确定随后对乙醇的反应性改变的机制。*拟议的实验将检验以下观察结果：胎儿时期接触乙醇的个体在青少年和成人时期更有可能滥用乙醇，胎儿接触乙醇是否会使乙醇在以后更有价值和可接受性，以及这些影响是如何由鸦片系统介导的。

DESCRIPTION (provided by applicant): Use of ethanol during or just before adolescence clearly predicts ethanol abuse later in life. Is this ethanol use in adolescence due to still earlier exposure to ethanol? Epidemiological evidence in humans and experiments with rats indicate that ethanol acceptance in adolescence is potentiated by prenatal exposure to ethanol. The present proposal tests the hypothesis that a few moderate, nonteratological doses of ethanol during late gestation alters later responsiveness to ethanol, including ethanol acceptance and reinforcement from birth to adolescence and activating effects of ethanol during adolescence. This hypothesis is encouraged by preliminary studies indicating that this prenatal ethanol exposure not only increases later ethanol acceptance but also increases the range of appetitively reinforcing ethanol doses. In each of the proposed experiments postnatal responsiveness to ethanol will be assessed for animals given 0, 1 or 2 g/kg on each of gestational days 17-20 or a control treatment. Specific Aim 1 is to test ethanol intake and ethanol reinforcement soon after birth, in terms of three different reinforcement paradigms. Specific Aim 2 is to test effects of .prenatal ethanol on ethanol acceptance and ethanol reinforcement in adolescence and at a point midway between birth and adolescence (postnatal day 15, P15). Specific Aim 3 is to test the consequences of prenatal ethanol exposure for an established activating effect of ethanol during adolescence, ethanol- induced social facilitation. In view of the apparent role of the endogenous opioid system in ethanol ingestion, ethanol reinforcement and adolescent social behavior, Specific Aim 4 is to test the effects of prenatal ethanol on beta-endorphin gene expression, beta-endorphin brain levels and ?-opioid receptor binding associated with ethanol ingestion, ethanol reinforcement, and ethanol-induced social behavior. These tests will occur soon after birth, on P15 or during adolescence. The intention is to clarify the ontogeny of risk from moderate exposure to prenatal ethanol and determine mechanisms underlying subsequently altered responsiveness to ethanol. *Proposed experiments will test the observation that individuals exposed to ethanol as fetuses are more likely to abuse ethanol as adolescents and adults, whether this fetal exposure makes ethanol more rewarding and acceptable later on, and how these effects might be mediated by the opiate system.