Inhibitory Synaptic Transmission and Drugs of Abuse

描述(由申请人提供)：这项建议将继续我们的工作，检查突触可塑性在腹侧被盖区(VTA)神经元对滥用药物的反应中的作用，使用电生理学和药理学工具。我们的研究将在两个层面上做出贡献。首先，拟议的实验将定义这一大脑区域的基本突触和电路特性，这是在生理条件下处理奖赏和厌恶刺激所必需的。其次，我们将在体外和体内将这些突触和回路特性与^-阿片类药物的反应联系起来。我们特别感兴趣的是定义VTA功能的变化，这些变化可能是导致其成瘾特性的候选机制。在这个应用中，我将探索抑制性VTA突触在^-阿片类药物反应中的作用。大约20-30%的VTA神经元是GABA能神经元，阿片类药物和乙醇几乎完全与GABA能神经元和GABA受体功能相互作用。GABA激动剂或拮抗剂进入VTA是有益的，并有力地影响对成瘾药物的行为反应。此外，反复暴露于可卡因或吗啡改变了大鼠VTA神经元上GABAB受体突触的突触功能，单次接触乙醇改变了GABAA受体突触向VTA多巴胺神经元的传递。阿片类药物的长期治疗改变了VTA电路被奖励刺激激活的方式，这与VTA中GABA能受体功能的变化有关。首先，我们将比较多巴胺神经元和GABA能神经元上的突触。然后，我们将检测阿片类药物对相关VTA突触的GABA能传递的快速影响，最后，我们将在体内用吗啡处理动物，然后测试脑片中的GABA能突触传递，看看GABAA突触传递是否发生了变化。我们还将定义我们最近发现的新的GABA能突触传递的LTP的性质，并测试急性或活体用-阿片类药物治疗对IPSC LTP的影响。我希望我们的工作能阐明阿片类化合物改变大脑这一区域的正常功能的细胞机制，这一区域对正常的奖赏处理至关重要。

DESCRIPTION (provided by applicant): This proposal will continue our work examining the role of synaptic plasticity in the response of ventral tegmental area (VTA) neurons to drugs of abuse, using electrophysiological and pharmacological tools. Our studies will contribute at two levels. First, the proposed experiments will define the basic synaptic and circuit properties of this brain region, essential for processing rewarding and aversive stimuli under physiological conditions. Second, we will link these synaptic and circuit properties with responses to ^-opioids in vitro and in vivo. We are especially interested in defining alterations in VTA function that may be candidate mechanisms contributing to their addictive qualities. In this application, I will explore the role of inhibitory VTA synapses in responses to ^-opioids. About 20- 30% of VTA neurons are GABAergic, and opioids and ethanol interact almost exclusively with GABAergic neurons and GABA receptor function. GABA agonists or antagonists delivered into the VTA are rewarding and powerfully influence behavioral responses to addictive drugs. Furthermore, repeated exposure of rats to either cocaine or morphine alters synaptic function at GABAB receptor synapses on VTA neurons, and a single exposure to ethanol alters GABAA receptor synaptic transmission onto VTA dopamine neurons. Chronic treatment with opioids alters the way the VTA circuit is activated by rewarding stimuli, and this is correlated with changes in GABAergic receptor function in the VTA. First we will compare synapses on dopamine neurons with those on GABAergic neurons. We will then examine rapid effects of opioids on GABAergic transmission at relevant VTA synapses, and finally, we will treat animals with morphine in vivo and then test GABAergic synaptic transmission in brain slices to see if changes in GABAA synaptic transmission have occurred. We will also define the properties of the novel LTP of GABAergic synaptic transmission we have recently discovered, and test the effects on IPSC LTP of acute or in vivo treatment with ^-opioids. I expect our work to elucidate the cellular mechanisms by which opioid compounds alter the normal function of this brain area essential for normal reward processing.