NOVELTY, DOPAMINE AND RESPONSE TO AMPHETAMINE

我们的总体工作假设是，暴露于新的刺激以类似于滥用药物的方式激活中脑边缘多巴胺（DA）奖励通路。为了支持这一假设，我们现在有明确的神经化学证据表明，新奇事物激活了大鼠的中边缘DA系统。在行为水平上，我们还发现，断奶后在充满新刺激的环境中长大的大鼠，与隔离环境中长大的大鼠相比，成年后静脉注射安非他明的自我管理减少。然而，目前尚不清楚安非他明自我给药的减少是否反映了环境诱导的中脑边缘DA活性的改变，也不知道在青年期短暂接触新鲜事物是否也会减少安非他明的自我给药。本项目将确定发展过程中的环境富集是否会改变中边缘DA活动。体内伏安法和电生理记录技术，以及体外细胞技术，将被用来回答这个问题。这些神经化学实验将从伏隔核开始，尽管其他大脑区域（如前额叶皮质、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，环境诱导的安非他明自我给药的差异将使用固定比率和渐进比率强化时间表进行检验。对照实验将确定在安非他明自我给药中观察到的环境诱导差异是否可以推广到蔗糖强化。最后，我们将研究在青年时期短暂接触新鲜事物是否也会减少安非他明的自我给药。基于我们的工作假设，我们预测新鲜感将取代安非他明奖励。如果新颖性减少了大鼠对安非他明的自我给药，这一临床前信息将为检验在人类药物滥用预防和/或治疗干预中呈现高度新颖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学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.