MOP Receptor Effects on the Hippocampal CA1 Network

描述（由申请人提供）：阿片类药物使用者的高复发率通常是由暴露于与既往药物使用相关的环境线索引发的。这些关联被认为涉及海马内μ阿片肽（MOP）受体的激活。海马内GABA能抑制性中间神经元上的MOP受体活化抑制GABA释放到锥体细胞上，这可以深刻地影响海马网络功能并调节到CNS其他区域的信息流。正是海马网络功能的这种变化，可能参与了环境线索和慢性药物滥用之间联系的形成。虽然已知MOP受体激活抑制GABA能突触传递，但MOP受体激活抑制的确切中间神经元及其对海马CA1网络功能的特异性影响尚未完全了解。基于初步研究，我们假设MOP受体抑制GABA从支配整个体细胞和树突程度的CA1锥体细胞的中间神经元的释放。此外，我们认为，MOP受体激活增强兴奋性输入，促进锥体细胞室之间的兴奋性信息的传播，并促进CA1网络内的兴奋性活动的时间和空间整合。MOP受体对海马CA1网络功能的影响将使用来自大鼠脑切片的电压敏感染料（VSD）成像来检查。VSD成像将使我们能够同时测量整个海马CA1脑切片神经网络的兴奋性和抑制性活动，具有高的空间和时间分辨率。这些研究将为解决长期阿片类药物使用如何改变MOP受体和神经网络功能的长期目标提供基础。这些研究的结果将提供有关MOP受体诱导的网络活动变化的重要信息，并可能导致阿片类药物成瘾治疗的发展。

DESCRIPTION (provided by applicant): The high rate of relapse in opioid drug users is often triggered by the exposure to environmental cues associated with previous drug use. These associations are thought to involve the activation of mu-opioid peptide (MOP) receptors within the hippocampus. MOP receptor activation on GABAergic inhibitory interneurons within the hippocampus inhibits the release of GABA onto pyramidal cells, which can profoundly affect hippocampal network function and modulate the flow of information to other areas of the CNS. It is this change in hippocampal network function that may be involved in the formation of the associations made between environmental cues and chronic drug abuse. Although it is known that MOP receptor activation inhibits GABAergic synaptic transmission, the precise interneurons inhibited by MOP receptor activation and their specific effect on hippocampal CA1 network function is not completely understood. Based on preliminary studies, we hypothesize that MOP receptors inhibit the release of GABA from interneurons that innervate the entire somatic and dendritic extent of CA1 pyramidal cells. Furthermore, we suggest that MOP receptor activation augments excitatory inputs, facilitates the propagation of excitatory information between pyramidal cell compartments, and facilitates the temporal and spatial integration of excitatory activity within the CA1 network. The effects of MOP receptors on hippocampal CA1 network function will be examined using voltage-sensitive dye (VSD) imaging from rat brain slices. VSD imaging will allow us to simultaneously measure both excitatory and inhibitory activity throughout the entire neural network of hippocampal CA1 brain slices with high spatial and temporal resolution. These studies will provide a foundation to address the long-term goals of how chronic opioid use alters MOP receptor and neural network function. The results from these studies will provide important information regarding MOP receptor-induced changes in network activity and may possibly lead to the development of treatments for opioid addiction.