Facilitating Extinction in Adolescents

描述（由申请人提供）：当我们奋进了解药物寻求的机制和治疗途径时，解决独特的人群至关重要。发育中的大脑对兴奋剂等滥用药物的反应不同，在青春期有一个特别容易上瘾的窗口。寻求毒品行为的灭绝是药物成瘾治疗的一个组成部分，最近我们报道说，相对于成年人，青少年对灭绝的抵抗力更强。重要的是，青春期也是一个关键的发展时期，在这一时期，干预措施可以防止终生复发的吸毒成瘾。近年来的研究表明：1）青少年是药物成瘾的易感人群，其觅药行为的消退具有延迟性; 2）觅药行为的消退和复吸是由动机条件反射介导的; 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，和4）青少年PFC内的多巴胺受体分布是独特的。拟议的实验将建立在我们最近的观察，即D1多巴胺受体是短暂的PFC输出过度产生的青春期的脑桥核。本申请将这些发现应用于一个工作假设，可能会导致针对青少年的新的治疗策略。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。 公共卫生相关性：青春期是大脑皮层发育的一个独特阶段，特别容易对药物成瘾。对药物相关线索的反应增强，对较弱刺激的反应能力减弱，使青少年对寻求药物的灭绝产生抵抗力。因此，在大脑发育的这一关键时期治疗药物成瘾将需要与成人不同的策略，例如皮质靶向药物干预。

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.