Inhibitory Synaptic Transmission and Drugs of Abuse

这个建议将继续我们的工作，研究突触可塑性在腹侧反应中的作用。 被盖区（VTA）神经元滥用药物，使用电生理学和药理学工具。我们 研究将在两个层面作出贡献。首先，拟议的实验将定义基本的突触和电路 这个大脑区域的特性，在生理条件下对处理奖励和厌恶刺激至关重要。 条件其次，我们将这些突触和回路特性与体外对^-阿片类药物的反应联系起来， in vivo.我们特别感兴趣的是定义VTA功能的改变， 导致其成瘾性的机制。 在本申请中，我将探索抑制性腹侧被盖区突触在^-阿片类药物反应中的作用。大约20- 30%的腹侧被盖区神经元是GABA能神经元，阿片类药物和乙醇几乎只与GABA能神经元相互作用 神经元和GABA受体功能。GABA激动剂或拮抗剂输送到腹侧被盖区是有益的 并有力地影响对成瘾药物的行为反应。此外，大鼠反复暴露于 可卡因或吗啡改变VTA神经元上GABAB受体突触的突触功能， 单次暴露于乙醇改变GABAA受体突触传递到腹侧被盖区多巴胺神经元。 阿片类药物的长期治疗改变了VTA回路被奖励刺激激活的方式，这是 与腹侧被盖区GABA能受体功能变化相关。首先，我们将比较 多巴胺能神经元与GABA能神经元上的那些。然后，我们将研究阿片类药物对 GABA能在相关VTA突触的传递，最后，我们将在体内用吗啡治疗动物 然后在大脑切片中测试GABA能突触传递，看看GABA A突触传递的变化是否与大脑切片中的GABA能突触传递有关。 传输已经发生。我们还将定义GABA能突触LTP的新特性， 我们最近发现了IPSC LTP的传播，并测试了急性或体内治疗对IPSC LTP的影响 阿片类药物。我希望我们的工作能够阐明阿片类化合物改变细胞的机制。 这一大脑区域的正常功能对正常的奖励处理至关重要。

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.