A method to assess alcohol discrimination in adolescents

描述（由申请人提供）：青春期是一个关键的发展时期，在此期间，酒精的使用往往开始。除了在这个敏感的发育时期酒精暴露可能对大脑产生有害影响外，青少年饮酒还与成年后依赖风险增加有关。因此，了解青少年饮酒的机制至关重要。在青春期和成年期饮酒增加的一个可能的行为机制是对酒精内感受性影响的敏感性降低。所有滥用药物都有一个共同的属性，即它们在人类和动物中产生内感受/主观效应，这些内感受效应是药物寻求行为和滥用倾向的主要控制过程。酒精和其他药物的内感受性作用通常使用操作性药物辨别方法在动物中测量，其中动物被训练来辨别药物和非药物内感受性线索。到目前为止，酒精和药物滥用领域还没有适当的工具来充分评价啮齿动物短暂青春期的药物内感受性影响。这部分是由于实际药物鉴别技术所需的培训程序冗长。因此，对青春期内感受性药物的影响知之甚少。为了解决这一知识差距，本提案中的研究纳入了巴甫洛夫歧视培训方法。这个过程是理想的评估内感受性影响的酒精在一个很短的发展窗口，因为我们在初步研究中显示，大鼠迅速获得的歧视在一个时间框架，跨越青少年发育期。本申请中的研究有两个独立但综合的具体目标。在具体目标1中，实验使用巴甫洛夫辨别程序评估了青少年对酒精内感受性影响的敏感性。青春期是GABA能和NMDA受体系统发生神经化学重塑和成熟的关键时期。有趣的是，这些系统是已知的酒精药物线索（在成人）使用操作性辨别技术的主要组成部分。因此，实验将确定机制参与GABAA和NMDA受体相关系统的差异敏感性酒精。从这些研究中获得的信息可能表明青少年饮酒增加的行为机制。也就是说，青少年可能会喝更多的酒，因为他们对饮酒的内感受性影响不太敏感。此外，鉴于内感受性药物效应是滥用倾向的主要决定因素，在青春期经历酒精的影响可能会改变成年后对酒精暗示的看法。因此，巴甫洛夫辨别程序的另一个优点是，可以直接比较青春期和成年期对酒精的敏感性。因此，在具体目标2中，实验将研究在青春期经历酒精后，成年期对酒精线索的敏感性是否会改变。此外，鉴于青春期GABA能和NMDA能机制的发育变化，还将检查潜在机制（GABA或NMDA相关系统）。总之，本提案中的探索性和高度新颖的研究，结合了一种尚未用于检查酒精内感受性影响的训练方法，旨在扩展我们对酒精在青春期内感受性影响的理解，并可能有助于一种行为机制，可以告知我们对青春期饮酒的理解以及成年后饮酒风险的增加。

DESCRIPTION (provided by applicant): Adolescence is a critical developmental period during which alcohol use is often initiated. In addition to the detrimental effects that alcohol exposure can have on the brain during this sensitive developmental period, adolescent alcohol use is also associated with increased risk of dependence in adulthood. Thus, understanding the mechanisms underlying adolescent drinking is critical. A possible behavioral mechanism for increased alcohol drinking during adolescence and later in adulthood is diminished sensitivity to the interoceptive effects of alcohol. All drugs of abuse share the common attribute that they produce interoceptive/subjective effects in humans and animals, and these interoceptive effects are a major controlling process of drug seeking behavior and abuse liability. The interoceptive effects of alcohol and other drugs are routinely measured in animals using operant drug discrimination methods, in which animals are trained to discriminate between drug and non-drug interoceptive cues. To date, the alcohol and drug abuse field has not had the appropriate tools by which to adequately evaluate drug interoceptive effects during the brief adolescent period in rodents. This is due, in part, to the lengthy training procedures required in operant drug discrimination techniques. As such, little is known about interoceptive drug effects in adolescence. To address this gap in knowledge, the studies in this proposal incorporate a Pavlovian discrimination training method. This procedure is ideal for assessment of the interoceptive effects of alcohol within a short developmental window because as we show in Preliminary Studies, the rats quickly acquire the discrimination in a time frame that spans the adolescent developmental period. The studies in this application have two separate but integrated Specific Aims. In Specific Aim 1, experiments assess sensitivity to the interoceptive effects of alcohol in adolescents using the Pavlovian discrimination procedure. Adolescence is a critical period during which GABAergic and NMDA receptor systems undergo neurochemical remodeling and maturation. Interestingly, these systems are known to be major components of the alcohol drug cue (in adults) using operant discrimination techniques. Therefore, experiments will determine mechanistic involvement of GABAA and NMDA receptor-related systems underlying differential sensitivity to alcohol. The information gained from these studies could suggest a behavioral mechanism for increased alcohol drinking by adolescents. That is, adolescents may drink more alcohol because they are less sensitive to the interoceptive effects of the consumed alcohol. Further, given that interoceptive drug effects are a primary determinant of abuse liability, it is possible that experiencing the effects of alcohol during adolescence alters the perception of the alcohol cue in adulthood. Accordingly, another advantage of the Pavlovian discrimination procedure is that direct comparison between sensitivity to alcohol in adolescence and later in adulthood can be made. Thus, in Specific Aim 2, experiments will examine whether sensitivity to the alcohol cue in adulthood is altered after experiencing alcohol in adolescence. Further, given the developmental changes in GABAergic and glutamatergic mechanisms during adolescence the underlying mechanism (GABA or NMDA-related systems) will also be examined. Together, the exploratory and highly novel studies in this proposal, that incorporate a training method that has not been utilized to examine the interoceptive effects of alcohol, aim to extend our understanding of the interoceptive effects of alcohol in adolescence, and potentially contribute a behavioral mechanism that can inform our understanding of alcohol drinking in adolescence and increased risk for alcohol use in adulthood.