Facilitating Extinction in Adolescents

描述(由申请人提供)：当我们努力了解寻求药物的机制和治疗途径时，解决独特的人群是至关重要的。发育中的大脑对兴奋剂等滥用药物的反应不同，在青春期有一个特别容易上瘾的窗口。戒除寻找毒品的行为是药物成瘾治疗中不可或缺的一部分，最近我们报道了青少年相对于成年人对戒毒行为的抵抗力。重要的是，青春期也代表着一个发展的关键时期，在这个时期，干预可以防止终生复发的毒瘾。最近，研究集中在以下几个观点上：1)青少年是药物成瘾的弱势群体，并表现出延迟的寻求行为消退；2)寻求药物的消失和复发是通过动机条件反射电路调节的；3)前额叶皮质(PFC)内的多巴胺能受体微电路介导动机条件反射；4)PFC内的青少年多巴胺受体图谱是独特的。拟议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伏隔核的PFC输出上短暂过度产生的基础上。这一应用将这些发现应用于一个可能导致针对青少年的新治疗策略的工作假说。这些研究为青少年吸毒成瘾治疗的关键研究奠定了基础，重点是消除寻求毒品的行为。 与公共卫生的相关性：青春期是大脑皮层发育的一个独特阶段，这导致对药物成瘾的特别脆弱性。青少年对毒品相关线索的反应增强，对较弱刺激的反应能力减弱，使青少年对寻求毒品的消亡产生抵抗力。因此，在大脑发育的这个关键时期治疗药物成瘾将需要不同于成人使用的策略，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.