Age differences in ethanol discrimination: Role of GABA-A and NMDA receptors

青春期是一个发育期，在此期间大量使用酒精是很常见的。使用青春期啮齿动物模型的研究观察到了与年龄相关的对酒精许多特性的敏感性差异，包括青少年对酒精诱导的社会促进的敏感性比成年人更高，但对酒精引起的运动障碍、镇静和烦躁不安的敏感性减弱。这种敏感度的年龄差异表明，青少年和成年人对酒精的主观影响可能有不同的看法。酒精辨别程序已被广泛用于深入了解乙醇的相互感觉(即主观)特性，但使用这种程序的研究在很大程度上忽视了青少年对象。利用已建立的青春期动物模型，这项拟议的工作旨在利用巴甫洛夫条件药物辨别程序来表征青春期大鼠相对于成年大鼠的酒精线索，该程序适合在相对较短的青春期发育期内测试动物。这一程序将考虑到酒精敏感性的年龄差异，比较青少年和成年人在各种训练条件下获得的歧视。鉴于GABAA和NMDA受体系统已被确定为成年动物乙醇线索的主要贡献者，精神药理学研究将通过测试乙醇替代试验中特定亚基的化合物，并使用mRNA和蛋白质分析来量化不同年龄特定脑区的亚单位表达，来研究各年龄段动物乙醇线索中GABAA和NMDA亚基组成的发育变化所起的作用。

Adolescence is a developmental period during which high ethanol use is common. Studies using rodent models of adolescence have observed age-related differences in sensitivity to many of ethanol's properties, including greater sensitivity of adolescents than adults to ethanol-induced social facilitation, but attenuated sensitivity to ethanol- induced motor impairment, sedation, and dysphoria. Such age discrepancies in sensitivity suggest that adolescents and adults may perceive ethanol's subjective effects differently. Ethanol discrimination procedures have been used extensively to gain insight into the interoceptive (i.e., subjective) properties of ethanol, but studies using such procedures have largely neglected adolescent subjects. Using an established animal model of adolescence, the proposed work aims to characterize the ethanol cue in adolescent rats relative to adults using a Pavlovian conditioned approach drug discrimination procedure amenable to testing animals within the relatively short developmental period of adolescence. This procedure will allow for comparison of discrimination acquisition in adolescents and adults under a variety of training conditions that will take into account age differences in ethanol sensitivity. Given that GABAA and NMDA receptor systems have been identified as major contributors to the ethanol cue in adult animals, psychopharmacological studies will then examine the role of developmental alterations in GABAA and NMDA subunit composition in the ethanol cue in animals of each age by testing subunit-specific compounds in ethanol substitution tests and quantifying subunit expression in specific brain regions across age using both mRNA and protein assays.