Inhibitory Synaptic Transmission and Drugs of Abuse

抑制性突触传递和滥用药物

• 批准号: 7799885
• 负责人: Julie A. Kauer
• 金额: $ 28.84万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-07-15 至 2012-01-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7799885
• 关键词: Acute; Animals; Area; Aversive Stimulus; Brain; Brain region; Chronic; Cocaine; Dopamine; Ethanol; Exposure to; GABA Agonists; GABA Receptor; In Vitro; Inhibitory Synapse; Link; Mediating; Morphine; Neurons; Opioid; Pharmaceutical Preparations; Physiological; Property; Rattus; Rewards; Role; Signal Transduction; Slice; Stimulus; Synapses; Synaptic Transmission; Synaptic plasticity; Testing; Ventral Tegmental Area; Work; behavior influence; dopaminergic neuron; drug of abuse; in vivo; interest; neural circuit; novel; receptor; receptor function; research study; response; reward processing; synaptic function; tool; transmission process

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.

这项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。 利用电生理学和药理学手段，对被盖区(VTA)神经元进行药物滥用。我们的 研究将在两个层面上做出贡献。首先，拟议的实验将定义基本的突触和回路 在生理状态下处理奖赏和厌恶刺激所必需的这一大脑区域的特性 条件。其次，我们将在体外将这些突触和回路特性与^-阿片类药物的反应联系起来。 在活体内。我们特别感兴趣的是定义VTA函数中可能是候选的更改 导致他们上瘾的机制。 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。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能神经元相互作用 神经元和GABA受体的功能。GABA激动剂或拮抗剂进入VTA是有回报的 并强烈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 单一的乙醇暴露改变了GABA受体对VTA多巴胺神经元的突触传递。 阿片类药物的长期治疗改变了VTA回路被奖赏刺激激活的方式，这是 与VTA内GABA能受体功能变化相关。首先，我们将比较突触 多巴胺神经元和GABA能神经元上的神经元。然后我们将检查阿片类药物对 相关VTA突触的GABA能传递，最后，我们将在体内用吗啡治疗动物 然后在脑片中测试GABA能突触传递，看看GABA能突触的变化 已经发生了传播。我们还将定义新的GABA能突触的LTP的性质 我们最近发现的传播，并测试急性或体内治疗对IPSC LTP的影响 使用^-阿片类药物。我期待着我们的工作能够阐明阿片类化合物改变细胞功能的细胞机制。 这一脑区的正常功能对正常的奖赏处理是必不可少的。