Facilitating Extinction in Adolescents

描述（由申请人提供）：当我们努力了解药物寻找的机制和治疗途径时，解决特殊人群是至关重要的。发育中的大脑对兴奋剂等滥用药物的反应不同，在青少年时期容易上瘾。药物寻求行为的消除是药物成瘾治疗的一个组成部分，最近我们报道了青少年相对于成年人对药物寻求行为的消除更具抵抗力。重要的是，青春期也是一个关键的发展时期，在这个时期，干预可以防止终身复发的毒瘾。近年来，研究已集中于以下观点：1)青少年是药物成瘾的易感人群，表现出药物寻求行为的延迟消退；2)药物寻求行为的消退和复发是通过动机条件反射回路介导的；3)前额叶皮层（PFC）内的多巴胺能受体微回路介导动机条件反射；4)青少年PFC内的多巴胺受体谱具有独特性。提出的实验将建立在我们最近观察到的D1多巴胺受体在青春期向伏隔核输出的PFC上短暂过量产生的基础上。该应用程序将这些发现应用于一个工作假设，可能导致针对青少年的新治疗策略。这些研究为青少年药物成瘾治疗的关键研究奠定了基础，重点是消除寻求药物的行为。

DESCRIPTION (provided by applicant): As we endeavor to understand the mechanisms and treatment avenues for drug seeking, it is crucial to address unique populations. The developing brain responds differently to drugs of abuse such as stimulants, with a particular window of vulnerability for addiction in adolescence. Extinction of drug-seeking behavior is an integral part of drug addiction treatment, and recently we reported that adolescents are more resistant to extinction relative to adults. Importantly, adolescence also represents a critical period of development when intervention could prevent a lifetime of recurring drug addiction. Recently, research has converged on the ideas that, 1) adolescents are a vulnerable population for drug addiction and display delayed extinction of drug seeking behaviors, 2) extinction and relapse of drug-seeking are mediated through motivational conditioning circuitries, 3) the dopaminergic receptor microcircuitry within the prefrontal cortex (PFC) mediates motivational conditioning, and 4) the adolescent dopamine receptor profile within the PFC is unique. The proposed experiments will build on our recent observation that the D1 dopamine receptor is transiently overproduced on PFC outputs to the nucleus accumbens during adolescence. This application applies these findings to a working hypothesis that may lead to novel treatment strategies targeted to adolescents. These studies serve as a foundation for a crucial line of research into the treatment of adolescent drug addiction, focusing on the extinction of drug-seeking behavior. PUBLIC HEALTH RELEVANCE: Adolescence represents a unique stage of cortical development which results in a particular vulnerability to drug addiction. Heightened responsiveness to drug- associated cues, and diminished ability to respond to less-potent stimuli, render adolescents resistant to extinction of drug-seeking. Therefore, treatment of drug addiction during this critical period of brain development will require distinct strategies from those used for adults, such as cortically-targeted pharmacologic intervention.