MOP Receptor Effects on the Hippocampal CA1 Network

描述(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先前药物使用有关的环境线索引发的。这些联系被认为涉及到海马体内阿片肽受体的激活。激活海马内GABA能抑制中间神经元上的MOP受体可以抑制GABA向锥体细胞的释放，这可以深刻地影响海马网络功能，并调节信息流向中枢其他区域。正是这种海马体网络功能的改变可能参与了环境线索和慢性药物滥用之间的联系的形成。尽管已知MOP受体激活可抑制GABA能突触传递，但MOP受体激活所抑制的确切中间神经元及其对海马CA1区网络功能的具体作用尚不完全清楚。在初步研究的基础上，我们假设MOP受体抑制了支配CA1锥体细胞整个体细胞和树突的中间神经元释放GABA。此外，我们认为，MOP受体的激活增加了兴奋性输入，促进了兴奋信息在锥体细胞间的传递，并促进了兴奋活动在CA1网络中的时空整合。我们将使用大鼠脑片的电压敏感染料(VSD)成像技术来检测MOP受体对海马CA1网络功能的影响。VSD成像将使我们能够以高空间和时间分辨率同时测量整个海马CA1脑片的整个神经网络的兴奋和抑制活动。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.