INDIVIDUAL DIFFERENCES IN RESPONSE TO AMPHETAMINE

最近的理论将药物滥用描述为一种不仅涉及积极激励动机的障碍， 一种以失去抑制性控制为特征的紊乱。在这个项目中，我们将使用一个实验室动物 模型来确定风险相关性状之间关联的关键神经机制 以及药物滥用，这些问题无法通过人类受试者得到充分解决。我们的假设是 个体在风险相关特征、奖励寻求和抑制方面的差异在药物滥用中发挥作用 脆弱性和这两种行为结构的个体差异是由可分离的 神经系统而奖赏寻求和抑制无疑涉及复杂和重叠的神经网络， 回路，我们目前的知识表明，奖励寻求是由上升中皮质边缘 多巴胺（DA）系统，而抑制是由涉及DA和 血清素（5-HT）。解剖学研究还表明，内侧前额叶皮层（mPFC）是 与奖赏寻求和抑制有关，而眶额皮质（OFC）与 抑制作用这些神经系统将被检查，以确定他们的作用，在协会的奖励 药物奖励的寻求和抑制。将评估大鼠在奖励寻求中的个体差异 和抑制使用各种行为测试，然后将评估安非他明奖励，DA和5- HT转运蛋白功能和通过体内伏安法和电生理学评估的神经活性 问题研究我们预测，高奖励寻求和低抑制的大鼠将最容易受到 安非他明和相关药物的奖励作用。同时，我们预测高奖赏的老鼠 寻求和低抑制将最敏感的非药物替代药物，与药物竞争 奖励，这可能对设计有效的药物滥用预防具有重要的转化影响 人类的干预策略。最后，我们预测，个体差异的奖励寻求和 这种抑制作用与中脑前额叶皮质内DA和5-HT系统的差异有关 和/或OFC。这些结果，结合人类行为药理学和神经成像结果， 项目2，将提供一个更全面的了解神经系统参与风险相关的特质 与设计有针对性的禁毒预防干预信息有关。

Recent theories describe drug abuse as a disorder involving not only positive incentive motivation, but as a disorder also charactered by a loss of inhibitory control. In this project, we will use a laboratory animal model to determine the critical neural mechanisms that underlie the association between risk-related traits and drug abuse, questions that cannot be addressed fully using human subjects. Our working hypothesis is that individual differences in the risk-related traits, reward seeking and inhibition, play a role in drug abuse vulnerability and that individual differences in these two behavioral constructs are mediated by dissociable neural systems. While reward seeking and inhibition undoubtedly involve complex and overlapping neural circuits, our current knowledge suggests that reward seeking is subserved by ascending mesocorticolimbic dopamine (DA) systems, whereas inhibition is subserved by frontal cortical regions involving both DA and serotonin (5-HT). Anatomical studies have also revealed that the medial prefrontal cortex (mPFC) is implicated in both reward seeking and inhibition, whereas the orbitofrontal cortex (OFC) is implicated in inhibition. These neural systems will be examined to determine their role in the association of reward seeking and inhibition with drug reward. Rats will be assessedfor individual differences in reward seeking and inhibition using a variety of behavioral tests and then will assessed for amphetamine reward, DA and 5- HT transporter function, and neural activity assessed by in vivo voltammetry and electrophysiological studies. We predict that rats that are high in reward seeking and low in inhibition will be most vulnerable to the rewarding effect of amphetamine and related drugs. Also, we predict that rats that are high in reward seeking and low in inhibition will be most sensitive to nondrug alternative reinforcers that compete with drug reward, which may have important translational implications for the design of effective drug abuse prevention intervention strategies in humans. Finally, we predict that individual differences in reward seeking and inhibition will be associatedwith differences in DA and 5-HT systems within the nucleus accumbens, mPFC and/or OFC. These results, combined with the human behavioral pharmacology and neuroimaging results in Project 2, will provide a more comprehensive understanding the neural systems involved in risk-related traits relevant to the design of tailored anti-drug prevention intervention messages.