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

青春期是一个发育时期，在此期间大量使用乙醇是很常见的。使用啮齿动物青少年模型的研究发现，青少年对乙醇许多特性的敏感性存在年龄相关差异，包括青少年对乙醇诱导的社交促进的敏感性高于成人，但对乙醇诱导的运动障碍、镇静和烦躁的敏感性较弱。这种年龄差异的敏感性表明，青少年和成年人可能感知乙醇的主观影响不同。乙醇辨别程序已被广泛用于深入了解乙醇的内感受性（即主观）特性，但使用此类程序的研究在很大程度上忽视了青少年受试者。利用已建立的青春期动物模型，本研究的目的是利用巴甫洛夫条件反射方法来表征青春期大鼠相对于成年大鼠的乙醇线索，该方法适用于在青春期相对较短的发育时期内测试动物的药物鉴别程序。这个程序将允许在各种训练条件下比较青少年和成人的歧视习得，这些条件将考虑到乙醇敏感性的年龄差异。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来源，精神药理学研究将通过在乙醇替代测试中测试亚基特异性化合物，并使用mRNA和蛋白质测定在不同年龄的特定脑区量化亚基表达，来检查GABAA和NMDA亚基组成在不同年龄动物乙醇线索中的发育改变的作用。

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.