Inhibitory synaptic transmission, stress, and drugs of abuse

描述（由申请人提供）：在本申请中，我们将描述突触可塑性在急性应激反应中的调节。特别是，我们将使用电生理和药理学工具和敲除小鼠来检查腹侧被盖区（VTA）的谷氨酸能和gaba能突触的长期增强，VTA是生理条件下处理奖励和厌恶刺激所需的关键区域，也是滥用药物成瘾所需的区域。我希望我们的研究在两个层面上有所贡献。首先，我们将定义应激后该大脑区域的基本突触和电路特性的变化。其次，我们将这些变化与压力诱导的药物寻求恢复联系起来。在这个应用程序中，我将重点关注压力对VTA突触的影响。首先，我们将确定在短暂的压力刺激后，VTA的细胞变化。我们将比较不同形式的应力，并测试应力对突触影响的时间过程。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，我们将利用这些实验中获得的分子信息来促进或阻断VTA体内的突触可塑性，同时评估短暂应激触发药物寻找恢复的能力。这些实验将首次验证这样一个假设，即在VTA中发生的突触变化是压力刺激引发药物寻求行为的必要条件。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，旨在干扰由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.