Inhibitory synaptic transmission, stress, and drugs of abuse

描述(申请人提供)：在本申请中，我们将描述突触可塑性对急性应激反应的调节。特别是，我们将使用电生理学和药理学工具以及基因敲除小鼠来检测腹侧被盖区(VTA)中谷氨酸和GABA能突触的长期增强作用，VTA是生理条件下处理奖赏和厌恶刺激所需的关键区域，也是滥用药物成瘾所必需的。我预计我们的研究将在两个层面上做出贡献。首先，我们将定义应激后大脑这一区域基本突触和回路属性的变化。其次，我们将把这些变化与压力诱导的毒品寻觅的恢复联系起来。在本应用中，我将重点研究应激对VTA突触的影响。首先，我们将确定短暂的应激刺激后VTA的细胞变化。我们将比较不同形式的应激，并测试应激对突触影响的时间进程。我们的初步数据表明，应激通过释放内源性阿片肽来改变VTA突触，我们将探索这一观点。最后，我们将使用在这些实验中获得的分子信息在体内促进或阻止VTA中的突触可塑性，同时评估短暂的应激触发药物寻找的恢复的能力。这些实验将首次验证这一假设，即VTA中发生的突触变化对于应激刺激诱导药物寻找行为是必不可少的。如果我的假设是正确的，我们的工作将为治疗提供新的分子靶点，旨在干扰压力引起的神经适应。

DESCRIPTION (provided by applicant): In this application, we will characterize the modulation of synaptic plasticity in response to acute stress. In particular, we will use electrophysiological and pharmacological tools and knockout mice to examine long-term potentiation of glutamatergic and GABAergic synapses in the ventral tegmental area (VTA), a key region required for processing rewarding and aversive stimuli under physiological conditions, and also required for addiction to drugs of abuse. I expect our studies to contribute at two levels. First, we will define alterations in the basic synaptic and circuit properties of this brain region after stress. Second, we will link these alterations to stress-induced reinstatement of drug-seeking. In this application, I will focus on the effects of stress on VTA synapses. First we will identify the cellular changes in the VTA that follow a brief stressful stimulus. We will compare different forms of stress and test the time course of stress effects on synapses. Our preliminary data suggest that stress modifies VTA synapses by releasing endogenous opioid peptides, and we will explore this idea. Finally, we will use the molecular information gained in these experiments to promote or block synaptic plasticity in the VTA in vivo while assessing the ability of a brief stress to trigger reinstatement of drug-seeking. These experiments will test for the first time the hypothesis that synaptic changes occurring in the VTA are essential for stressful stimuli to elicit drug-seeking behavior. If my hypothesis is correct, our work will suggest novel molecular targets for therapeutics designed to interfere with the neuroadaptations caused by stress.