Neural Mechanisms Underlying Individual Differences in 3,4-Methylenedioxymethamph

描述(由申请人提供)：3，4-亚甲基二氧基甲基苯丙胺(MDMA；摇头丸)是一种苯丙胺衍生物，在过去20年中吸毒率不断上升，特别是在青少年和青壮年人口中。临床和动物数据都表明，MDMA的使用模式和滥用该药物的可能性存在高度的个体差异。因此，拟议研究的总体目标是(A)进一步表征我们在大鼠身上观察到的与MDMA相关的行为的个体差异，(B)确定可预测随后的成瘾样行为的特定行为，以及(C)确定这些个体差异的神经基础。为此，我们将首先在我们最近开发的行为敏化范式中运行大鼠，在该范式中，我们操纵给药环境，使得只有大约一半的动物对MDMA表现出行为敏化。随后，我们将在复吸的动物模型中确定个体对MDMA的行为敏感度的差异是否与成瘾行为有关。最后，为了开始绘制复发到MDMA寻找行为的回路，我们将把这项行为测试与内侧前额叶皮质离散亚区的暂时利多卡因失活结合起来，内侧前额叶皮质是一个大脑区域，似乎是一个共同的解剖学基础，各种刺激通过它汇聚到一起，驱动药物寻找行为。这项拟议的研究结果应该为MDMA行为效应的个体差异背后的神经机制提供独特的见解。对与成瘾类行为相关的神经行为特征进行这些类型的临床前调查，对于开发改善人类药物滥用和成瘾的治疗策略至关重要。 公共卫生相关性：这项研究将有助于我们理解与动物对类似成瘾行为的易感性增加相关的神经和行为特征。因此，这些发现可能有助于开发更好的治疗人类药物滥用和成瘾的选择。

DESCRIPTION (provided by applicant): 3,4-Methylenedioxymethamphetamine (MDMA; ecstasy) is an amphetamine derivative that has seen an increasing abuse rate over the past two decades, particularly in adolescent and young-adult populations. Both clinical and animal data suggest that there is a high degree of individual variability in the pattern of MDMA use and in the drug's potential for abuse. Thus, the overall goals of the proposed research are to (a) further characterize the individual differences in MDMA-related behaviors that we have observed in rats, (b) determine the specific behaviors that are predictive of subsequent addiction-like behaviors, and (c) determine the neural underpinnings of these individual differences. To do this, we will first run rats in our recently developed behavioral sensitization paradigm in which we manipulate the context of drug administration such that only approximately half of the animals express behavioral sensitization to MDMA. Subsequently, we will determine if individual differences in behavioral sensitization to MDMA are related to addiction-like behaviors in an animal model of relapse. Finally, to begin mapping out the circuitry of relapse to MDMA- seeking behavior, we will combine this behavioral testing with temporary lidocaine inactivation of discrete sub-regions of medial prefrontal cortex, a brain region that appears to be a common anatomical substrate through which a variety of stimuli converge to drive drug-seeking behavior. Results of the proposed study should provide unique insight into the neural mechanisms underlying individual differences in the behavioral effects of MDMA. These types of preclinical investigations into the neurobehavioral traits that are related to addiction-like behaviors are crucial to developing improved treatment strategies for human drug abuse and addiction. PUBLIC HEALTH RELEVANCE: This research will contribute to our understanding of the neural and behavioral traits related to animals' increased vulnerability to addiction-like behaviors. Therefore, the findings may aid in the development of improved treatment options for human drug abuse and addiction.