Inhibitory synaptic transmission, stress, and drugs of abuse

描述（由申请人提供）：在本申请中，我们将表征响应于急性应激的突触可塑性的调节。特别是，我们将使用电生理学和药理学工具和敲除小鼠来检查腹侧被盖区（VTA）中GABA能和GABA能突触的长时程增强，VTA是在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。我希望我们的研究能在两个层面上做出贡献。首先，我们将确定压力后这个大脑区域的基本突触和电路特性的变化。第二，我们将把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，我将集中在压力对腹侧被盖区突触的影响。首先，我们将确定在短暂的压力刺激后腹侧被盖区的细胞变化。我们将比较不同形式的压力，并测试压力对突触影响的时间过程。我们的初步数据表明，压力通过释放内源性阿片肽来改变腹侧被盖区突触，我们将探讨这一想法。最后，我们将使用这些实验中获得的分子信息来促进或阻断体内VTA中的突触可塑性，同时评估短暂应激触发药物寻求恢复的能力。这些实验将首次检验腹侧被盖区发生的突触变化对应激刺激诱发药物寻求行为至关重要的假设。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，这些靶点旨在干扰由压力引起的神经适应。 公共卫生相关性：我们已经确定了大脑奖励和成瘾中心的细胞机制，称为腹侧被盖区（VTA），这可能有助于成瘾和滥用药物复发的发展。当腹侧被盖区暴露于成瘾性药物时，腹侧被盖区突触的变化会导致适应不良的神经元反应，这些反应似乎是有益的，并强烈地迫使对药物的行为反应。有趣的是，压力似乎能够引发成瘾药物后VTA中的一些相同细胞变化，这可能表明压力促进人类物质滥用者复发的一种方式。通过研究细胞对这些药物和压力的反应，我们可以更好地了解压力和成瘾的潜在机制，并通过促进药物成瘾的治疗来改善人类健康。

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. PUBLIC HEALTH RELEVANCE: We have identified a cellular mechanism in a reward and addiction center of the brain, called the ventral tegmental area (VTA), that could contribute to the development of addiction and relapse to drugs of abuse. When the VTA is exposed to an addictive drug, changes in the synapses of the VTA lead to maladaptive neuronal responses that appear to be rewarding and powerfully compel behavioral responses to drugs. Intriguingly, stress appears able to trigger some of the same cellular changes in the VTA seen after addictive drugs, perhaps suggesting a way that stress promotes relapse in human substance abusers. By studying the cellular responses to these drugs and to stress, we can better understand the mechanisms underlying stress and addiction and improve human health by contributing to treatments for drug addiction.