Inhibitory synaptic transmission, stress, and drugs of abuse

复吸是与药物成瘾治疗相关的一个核心问题。短暂的压力会 在人类中增强渴望并引发复发，在动物中引发强烈的药物寻求行为复发 模型过去十年来，我们实验室和其他实验室的最新研究表明， 成瘾性药物可以启动或阻断腹侧被盖区（VTA）的突触可塑性， 该区域是重新吸毒的关键区域。我们发现短暂的急性应激阻断了突触 VTA多巴胺神经元（LTPGABA）上GABA能突触的可塑性，并已表征了VTA多巴胺神经元（LTPGABA）的分子生物学特性。 涉及的级联。单一的压力体验会激活κ阿片受体（κORs），我们发现， 中断kappa受体信号可以挽救大脑切片记录中的LTP-但也重要的是， 压力导致的重新吸毒。我们最近发现，干扰κOR信号甚至 在应激后10天，在体外多巴胺神经元中挽救LTP，并防止药物恢复 在行为测试中寻找。虽然所有的机械步骤尚不清楚，但我们所有的数据都支持 一般的想法是，去除腹侧被盖区多巴胺神经元上的正常制动有助于恢复。在这 应用程序，我们将确定涉及的电路，问：1）GABA能传入通常表现LTPGABA 急性应激时哪些强啡肽释放传入和κORs处于激活状态 压力和改变腹侧被盖区回路来驱动复发行为。了解大脑区域和特定的通路 参与提供了机会，以操纵这些对治疗的发展。

Relapse is a central problem associated with the treatment of drug addiction. Exposure to brief stress can enhance craving and trigger relapse in humans, and triggers robust relapse to drug-seeking behavior in animal models. Recent work over the past ten years from our lab and others' has shown that a single exposure to an addictive drug can either initiate or block forms of synaptic plasticity in the ventral tegmental area (VTA), a region known to be critical in relapse to drug-seeking. We found that brief acute stress blocks synaptic plasticity at GABAergic synapses on VTA dopamine neurons (LTPGABA), and have characterized the molecular cascades involved. A single stressful experience activates kappa opioid receptors (κORs), and we showed that interrupting kappa receptor signaling rescues the LTP in brain slice recordings - but also importantly, prevents stress-induced reinstatement of drug-seeking. We have recently found that interrupting κOR signaling even days after the stressor both rescues LTP in dopamine neurons in vitro and prevents reinstatement of drug seeking in behavioral tests. While all the mechanistic steps are not yet known, all of our data support the general idea that removal of this normal brake on VTA dopamine neurons contributes to reinstatement. In this application, we will identify the circuits involved, asking: 1) which GABAergic afferents normally exhibit LTPGABA and lose it after acute stress, and 2) which dynorphin-releasing afferents and κORs are active during acute stress and alter the VTA circuit to drive relapse behavior. Knowing the brain regions and specific pathways involved offers the opportunity to manipulate these towards therapy development.