Ontogeny of Response to Ethanol After Prenatal Ethanol

描述(由申请者提供)：在青春期或青春期之前使用酒精清楚地预示着以后的生活中酒精滥用。这种在青春期使用乙醇的原因是不是因为更早接触乙醇？人类的流行病学证据和大鼠的实验表明，出生前接触乙醇会增强青春期对乙醇的接受。目前的建议验证了这样一种假设，即在妊娠晚期服用一些中等剂量的非畸形性酒精会改变后期对酒精的反应，包括从出生到青春期对酒精的接受和强化，以及在青春期酒精的激活效应。这一假设得到了初步研究的支持，初步研究表明，产前酒精暴露不仅增加了以后对酒精的接受，还增加了食欲增强的酒精剂量的范围。在每个拟议的实验中，将评估在怀孕17-20天的每一天给予0、1或2克/公斤的酒精或对照处理的动物出生后对酒精的反应性。具体目标1是测试酒精摄入量和酒精强化出生后不久，根据三种不同的强化范例。具体目标2是测试产前酒精对青春期和出生到青春期中间(出生后第15天，第15天)酒精接受度和酒精强化的影响。具体目标3是测试产前酒精暴露对酒精在青春期已有的激活作用的影响，即酒精诱导的社会促进作用。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，本研究的具体目的4是测试产前乙醇对与乙醇摄入、乙醇强化和乙醇诱导的社会行为相关的β-内啡肽基因表达、脑内β-内啡肽水平和β-阿片受体结合的影响。这些测试将在出生后不久、出生后15岁或青春期进行。其目的是阐明孕期适量接触乙醇的风险个体发生，并确定随后改变对乙醇的反应的潜在机制。*拟议的实验将测试以下观察结果：在胎儿时期接触乙醇的人在青少年和成年时更有可能滥用乙醇，这种胎儿时期的接触是否会使酒精在以后更有回报和更容易被接受，以及这些影响可能是如何由阿片系统调节的。

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.