Adolescent Cocaine Abuse: Electrophysiology & Behavior

描述(由申请人提供)：越来越多的人担心青春期与对精神刺激药物更敏感和成瘾风险增加有关。这种对药物自我给药敏感性的增加可能是因为与成人大脑相比，青春期大脑对反复药物暴露的反应或适应方式不同。这项建议的总体目标是通过啮齿动物模型了解导致青少年对可卡因自我给药易感性的神经生理和行为决定因素。多巴胺系统将是这些研究的重点，因为它在调节成瘾药物的奖赏效应方面发挥着核心作用。具体目的是：确定青春期是否以多巴胺细胞的兴奋性增强为特征，以及这是否由这些神经元的内在抑制特性降低(目标1)和/或对这些细胞的兴奋性突触输入增加(目标2)所介导。目的3将确定多巴胺神经元功能的变化是否会转化为可卡因自我给药行为的差异。通过这些目标，青少年和成年大鼠将在反复接触可卡因之前和之后进行比较，以评估个体是否表现出固有的差异，和/或表现出有助于自我管理行为的可卡因诱导的不同神经适应。神经活动将使用体内和体外电生理学技术进行评估；行为测试将包括各种自我给药程序，允许估计可卡因的奖励效应和自我给药的动机。总体而言，这项提案将使用多学科方法，从细胞水平到行为水平，研究青少年/成人可卡因自我给药差异的潜在机制。这些研究将使用与人类状况相关的行为模型，以深入了解青少年吸毒的原因和影响。从长远来看，这些发现将有助于制定治疗或预防可卡因成瘾的新的有针对性的治疗策略。

DESCRIPTION (provided by applicant): There is growing concern that adolescence is associated with greater sensitivity to psychostimulant drugs and increased risk of addiction. Such increased susceptibility to drug self-administration could be due to differences in the way the adolescent brain reacts or adapts to repeated drug exposure compared with the adult brain. The overall goal of this proposal is to understand the neurophysiological and behavioral determinants that contribute to adolescent susceptibility to cocaine self-administration, using rodent models. The dopamine system will be the focus of these studies, as it plays a central role in mediating the rewarding effects of addictive drugs. The specific aims are: to determine whether adolescence is characterized by heightened excitability of dopamine cells, and whether this is mediated by decreased intrinsic inhibitory properties of these neurons (Aim 1) and/or increased excitatory synaptic input to these cells (Aim 2). Aim 3 will establish whether changes in dopamine neuron function translate into differences in cocaine self-administration behavior. Throughout these aims, adolescent and adult rats will be compared both before and after repeated cocaine exposure to appraise whether individuals exhibit inherent differences, and/or show differential cocaine- induced neuroadaptations that could facilitate self-administration behavior. Neuronal activity will be assessed using in vivo and in vitro electrophysiology techniques; behavioral tests will consist of a variety of self-administration procedures that allow estimating the rewarding effects of cocaine and motivation to self-administer the drug. Overall, using a multidisciplinary approach this proposal will examine, from the cellular to the behavioral level, potential mechanisms underlying adolescent/adult differences in cocaine self-administration. These studies will use behavioral models that are relevant to the human condition to provide insight into both the causes and effects of adolescent drug use. In the long run, these findings will facilitate the development of new targeted therapeutic strategies for the treatment or prevention of cocaine addiction.