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乙醇滥用。青春期使用乙醇是否是因为更早接触乙醇？人类流行病学证据和大鼠实验表明，产前接触乙醇会增强青春期对乙醇的接受。目前的建议测试的假设，一些温和的，非致畸剂量的乙醇在妊娠后期改变以后对乙醇的反应，包括乙醇的接受和强化从出生到青春期和激活的影响，乙醇在青春期。初步研究表明，这种产前乙醇暴露不仅增加了后来的乙醇接受，而且增加了食欲增强乙醇剂量的范围，这一假设受到了鼓励。在每项拟定实验中，将评估妊娠第17-20天给予0、1或2 g/kg或对照处理的动物对乙醇的产后反应性。具体目标1是测试乙醇摄入量和乙醇强化出生后不久，在三个不同的强化范例。具体目标2是测试产前乙醇对青春期以及出生和青春期中间点（产后第15天，P15）乙醇接受和乙醇强化的影响。具体目标3是测试产前乙醇暴露对青春期乙醇激活效应（乙醇诱导的社会促进）的影响。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，具体目标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β-内啡肽的影响。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，P15或青春期进行。其目的是澄清产前适度暴露于乙醇的个体发育风险，并确定随后改变乙醇反应的机制。* 拟议的实验将测试以下观察结果：胎儿时期暴露于乙醇的个体更有可能在青少年和成年时滥用乙醇，这种胎儿暴露是否会使乙醇在以后更有益和更容易接受，以及阿片系统如何介导这些影响。

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.