A method to assess alcohol discrimination in adolescents

描述(申请人提供)：青春期是一个关键的发展时期，在此期间经常开始饮酒。除了在这一敏感的发育期接触酒精可能对大脑产生有害影响外，青少年饮酒也与成年后依赖的风险增加有关。因此，了解青少年饮酒的机制至关重要。青春期和成年后饮酒增加的一个可能的行为机制是对酒精的内感效应的敏感度降低。所有的滥用药物都有一个共同的属性，那就是它们在人和动物身上都产生了相互感觉/主观效应，这种相互感觉效应是毒品寻觅行为和滥用倾向的主要控制过程。酒精和其他药物的相互感觉效应在动物身上通常是使用操作性药物辨别方法来测量的，在这种方法中，动物被训练来区分药物和非药物相互感觉线索。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估啮齿动物短暂的青春期药物相互感觉的影响。这在一定程度上是由于操作毒品辨别技术所需的冗长培训程序。因此，人们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。这个程序非常适合在短的发育窗口内评估酒精的相互感觉效应，因为正如我们在《初步研究》中所展示的那样，大鼠在跨越青少年发育期的一段时间内迅速获得了辨别能力。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，实验使用巴甫洛夫歧视程序评估青少年对酒精互感效应的敏感性。青春期是GABA能和NMDA受体系统经历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的主要组成部分(在成年人中)，使用操作型辨别技术。因此，实验将确定GABAA和NMDA受体相关系统对酒精的差异敏感性的机制参与。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影响不那么敏感。此外，鉴于药物间感觉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线索的感知。因此，巴甫洛夫歧视程序的另一个优点是可以直接比较青春期和成年后对酒精的敏感性。因此，在特定的目标2中，实验将检查成年后对酒精暗示的敏感性是否在青春期经历了酒精之后发生了变化。此外，鉴于GABA能和谷氨酸能机制在青春期的发育变化，潜在的机制(GABA或NMDA相关系统)也将被研究。总之，这项提案中的探索性和非常新颖的研究纳入了一种尚未被用来检验酒精的内感效应的训练方法，旨在扩大我们对酒精在青春期的内感效应的理解，并潜在地贡献一种行为机制，可以让我们了解青春期饮酒和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.