Molecular Basis for Structural and Behavioral Effects of Chronic Opioid Exposure

项目总结 阿片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50,000人。目前可用的干预措施已被证明在以下方面无效 解决这一公共卫生危机。在过去的几十年里，在以下方面取得了重大进展 确定阿片类药物的神经机制。与其他滥用药物一样，阿片类药物激活了中脑边缘 多巴胺途径，增加腹侧被盖区多巴胺能神经元的兴奋性 以及通过投射到各种靶点来增强多巴胺的神经调节。中脑边缘药的作用 小鼠体内的多巴胺激活已经得到了很好的研究，其中包括增强的运动活动。一个VTA目标， 伏隔核(NAC)被认为是奖赏的“变阻器”，而多巴胺释放的波动 这个区域似乎控制着刺激是被认为是有益的还是令人厌恶的。除了严重的影响， 反复服用阿片类药物表明，这些药物不仅能够修饰多巴胺 释放还能诱导多巴胺反应的可塑性。例如，在一种被称为 精神运动敏感化，反复接触固定剂量的阿片类药物会逐渐增加 移动。作为一种与敏化相关的神经机制，阿片类药物已知可诱导脑细胞密度改变。 与NAc优势神经元群的突触接触，中棘投射神经元 (MSNS)。这些变化可能改变了NAC的内部电路动力学，以强调药物奖励和 强化，有助于发展成瘾和复发。然而，知识的匮乏 关于阿片类药物诱导的关键神经奖赏底物微电路的变化，提出了一种 旨在预防阿片类药物诱导突触的合理治疗设计的重大障碍 重新布线。MSN是异质性的，由至少两个亚群组成，可通过它们的 D1-多巴胺受体或D2-多巴胺受体的表达。D1-MSN似乎促进了成瘾 行为，而D2-MSN可能反对这些行为。尽管这些产品具有重要的功能 尽管存在差异，但阿片类药物诱导的形态变化的细胞类型特异性尚未得到调查。这个 拟议的实验将检验兴奋性和抑制性突触的亚型特异性结构可塑性。 NAC中的MSN作为对反复吗啡暴露的反应。然后我们将进行同样的评估 一个已知表现出弱化精神运动敏化的突变体中的参数，以确定亚型- 这种突变会导致特定的脊椎变化。

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.