Molecular Basis for Structural and Behavioral Effects of Chronic Opioid Exposure

项目摘要 阿片类药物成瘾是一种慢性复发性疾病，影响至少200万美国人， 年死亡率接近5万人目前可用的干预措施已被证明无效， 解决这场公共卫生危机。在过去几十年中， 确定阿片类药物的神经机制像其他滥用药物一样，阿片类药物激活中脑边缘系统 多巴胺通路，增加腹侧被盖区（VTA）多巴胺能神经元的兴奋性 以及通过投射到多种靶点来增强多巴胺神经调节。中脑边缘的影响 对小鼠中的多巴胺激活进行了充分的研究，并且包括增强的运动活性。一个VTA目标， 神经核（NAc）被认为是奖励的“变阻器”，多巴胺释放的波动在大脑中起着重要的作用。 该区域似乎控制刺激被感知为有益的还是厌恶的。除了急性反应， 阿片类药物的重复给药表明，这些药物不仅能够改变多巴胺 释放，但也诱导多巴胺反应的可塑性。例如，在一种被称为 精神敏化，重复暴露于固定剂量的阿片类药物会导致 运动作为致敏的神经相关物，已知阿片类药物诱导神经元密度的改变。 突触接触到NAc中的优势神经元群体，中等多刺投射神经元 （MSN）。这些变化可能会改变NAc的内部回路动力学，以强调药物奖励， 强化，有助于成瘾和复发的发展。然而，知识的缺乏 关于阿片类药物诱导的关键神经奖励底物微电路的变化， 合理设计旨在预防阿片类药物诱导的突触 重新布线MSN是异质性的，由至少两个亚群组成，可通过其 D1-多巴胺受体或D2-多巴胺受体的表达。D1-MSN似乎促进成瘾 行为，而D2-MSN可以反对这些行为。尽管这些功能的重要性 尽管存在差异，但尚未研究阿片类药物诱导的形态学变化的细胞类型特异性。的 拟议的实验将检查兴奋性和抑制性突触的亚型特异性结构可塑性 对重复吗啡暴露的反应。然后我们将评估相同的 已知表现出减弱的精神变态敏感性的突变体中的参数，以确定亚型- 特定的脊椎会因这种突变而改变

PROJECT SUMMARY Opioid addiction is a chronic relapsing disease affecting at least 2 million Americans with an associated annual mortality approaching 50,000 deaths. Currently available interventions have proven ineffective in addressing this public health crisis. Over the past several decades, significant progress has been made in identifying the neural mechanisms of opioids. Like other drugs of abuse, opioids activate the mesolimbic dopamine pathway, increasing the excitability of dopaminergic neurons in the ventral tegmental area (VTA) and enhancing dopamine neuromodulation via projections to a variety of targets. The effects of mesolimbic dopamine activation in mice are well studied and include heightened locomotor activity. One VTA target, the nucleus accumbens (NAc), is thought to act as a “rheostat” of reward, and fluctuations in dopamine release in this region appear to control whether stimuli are perceived as rewarding or aversive. Beyond acute effects, repeated administration of opioids demonstrates that these drugs are capable not only of modifying dopamine release but also of inducing plasticity in the dopamine response. For example, in a phenomenon known as psychomotor sensitization, repeated exposure to a fixed dose of opioid produces a progressive increase in locomotion. As a neural correlate of sensitization, opioids are known to induce alterations in the density of synaptic contacts onto the dominant neuronal population in the NAc, medium spiny projection neurons (MSNs). These changes likely modify the internal circuit dynamics of the NAc to accentuate drug reward and reinforcement, contributing to the development addiction and relapse. However, a dearth of knowledge concerning opioid-induced changes to the microcircuitry of key neural reward substrates presents a significant barrier to the rational design of therapies aimed at preventing opioid-induced synaptic rewiring. MSNs are heterogenous, consisting of at least two subpopulations, distinguishable by their expression of the D1-dopamine receptor or the D2-dopamine receptor. D1-MSNs appear to promote addictive behaviors while D2-MSNs may oppose these behaviors. Despite the functional significance of these differences, the cell-type specificity of opioid-induced morphologic changes has not been investigated. The proposed experiments will examine subtype-specific structural plasticity of excitatory and inhibitory synapses onto MSNs in the NAc in response to repeated morphine exposure. We will then evaluate the same parameters in a mutant known to exhibit attenuated psychomotor sensitization to determine whether subtype- specific spine changes by this mutation.