NOVELTY, DOPAMINE AND RESPONSE TO AMPHETAMINE

我们的总体工作假设是，暴露于新的刺激激活中脑边缘多巴胺（DA）奖励途径的方式类似于滥用药物。 为了支持这一假设，我们现在有明确的神经化学证据表明，新奇感激活了大鼠的中脑边缘DA系统。 在行为水平上，我们还发现，从断奶在一个环境中提出了丰富的新的刺激显示出减少静脉内安非他明自我管理的成年大鼠相比，在隔离。 然而，它是不知道，如果减少安非他明自我管理反映了环境引起的改变中脑边缘DA活性，也不知道，如果短暂暴露于新奇在年轻的成年期也将减少安非他明自我管理。本项目将确定在发展过程中环境富集是否会改变中脑边缘DA活性。 在体内伏安法和电生理记录技术，以及在体外细胞技术，将被用来回答这个问题。 这些神经化学实验将开始于脑桥核，尽管其他大脑区域（例如，前额叶皮层、扩展杏仁核、海马体）将在以后的研究中进行检查。 在行为水平上，环境引起的安非他明自我管理的差异将使用固定比例和渐进比例的强化时间表进行检查。 对照实验将确定安非他明自我给药时观察到的环境诱导的差异是否推广到蔗糖强化。 最后，我们将研究在年轻的成年期短暂接触新奇是否也会减少安非他明的自我管理。根据我们的工作假设，我们预测，新奇将取代安非他明奖励。 如果新奇减少了大鼠的安非他明自我给药，则该临床前信息将为检查在人类药物滥用预防和/或治疗干预中呈现高度新颖的刺激的有效性提供动力。 这项工作的长期目标是设计一种生物相关的预防干预策略，可以在对照人体研究中进行评估。

Our overall working hypothesis is that exposure to novel stimuli activates the mesolimbic dopamine (DA) reward pathway in a manner similar to drugs of abuse. In support of this hypothesis, we now have clear neurochemical evidence that novelty activates the mesolimbic DA system in rats. At the behavioral level, we also found that rats raised from weaning in an environment enriched with novel stimuli show a reduction in intravenous amphetamine self-administration as adults compared to rats raised in isolation. However, it is not known if the reduction in amphetamine self-administration reflects an environment-induced alteration in mesolimbic DA activity, nor is it known if brief exposure to novelty during young adulthood will also reduce amphetamine self-administration. The present project will determine if environmental enrichment during development alters mesolimbic DA activity. In vivo voltammetry and electrophysiological recording techniques, as well as in vitro cellular techniques, will be used to answer this question. These neurochemical experiments will begin with the nucleus accumbens, although other brain regions (e.g., prefrontal cortex, extended amygdala, hippocampus) will be examined in later studies. At the behavioral level, environment-induced differences in amphetamine self-administration will be examined using both fixed ratio and progressive ratio schedules of reinforcement. Control experiments will determine if environment-induced differences observed with amphetamine self- administration generalize to sucrose reinforcement. Finally, we will examine if brief exposure to novelty during young adulthood also reduces amphetamine self-administration. Based on our working hypothesis, we predict that novelty will substitute for amphetamine reward. If novelty reduces amphetamine self-administration in rats, this preclinical information would provide the impetus for examining the effectiveness of presenting highly novel stimulation in drug abuse prevention and/or treatment interventions in humans. The long-term objective of this work is to design a biologically relevant prevention intervention strategy that can be evaluated in a controlled human study.