Synaptic Reorganization in Drug Addiction

摘要 可卡因成瘾仍然是一个严重的医学和社会问题。一个突出的指导假设， 药物成瘾的分子和细胞研究是神经适应理论，它表明成瘾者 药物取代了通常帮助形成情景记忆的常见神经可塑性机制， 与成瘾有关的记忆尽管这一理论得到了药物之间惊人相似性的支持， 诱导的细胞适应和经验依赖的神经可塑性，它福尔斯在解释如何短 与成瘾有关的记忆非常持久，不会消失。以可卡因为药物模型， 在过去的几年里，我们已经开始解决这个关键问题，假设接触可卡因 “唤醒”休眠的，高效的细胞机制，否则只存在于发展中国家。 大脑深刻的改革特定的神经回路，导致极其持久的电路和行为 与成瘾有关的改变这一假设是基于我们最初的观察（发表于2009年） 暴露于可卡因会在丘脑核中产生大量沉默的兴奋性突触 壳层（NAc），一个重要的大脑区域的动机行为。沉默突触通常只含有NMDA 受体（NMDAR），AMPA受体（AMPAR）不存在或高度不稳定。因此，这些突触 在接近静息膜电位时通常“沉默”。在发育中的大脑中，许多沉默的突触是丰富的， 被认为是不成熟的突触接触;通过招募/稳定AMPAR成熟后，沉默的突触 可能会进化成功能齐全的突触，形成新的回路。因此，生成和潜在成熟 沉默的突触可能是暴露于可卡因恢复的关键发育机制之一， 引起持久的电路和行为改变。在广泛的兴奋性突触输入NAc， 来自内侧前额叶皮层（mPFC）的传入对大脑皮层的几个核心方面特别重要。 可卡因成瘾，包括可卡因自我给药（SA）戒断后的可卡因寻求和渴望。 我们目前的初步结果表明，沉默突触是在mPFC-to-NAc通路中产生的，并且 可卡因产生的沉默突触在这一途径中的成熟与 可卡因寻求的逐步加剧（可卡因渴望的潜伏期）。使用可卡因SA并寻求 作为动物模型，我们将测试可卡因SA招募发育机制的假设， 在成年大鼠脑中的mPFC至NAc通路内产生沉默突触;这些突触的成熟 在可卡因戒断过程中以及由此产生的mPFC至NAc途径的重组， 戒断相关的可卡因渴望和寻求。拟议研究的预期成果将公布 新的分子和细胞过程有助于可卡因复吸，并提供分子靶点， 潜在的临床治疗

Abstract Cocaine addiction remains a critical medical and social problem. A prominent guiding hypothesis for the molecular and cellular research of drug addiction is the neuroadaptation theory, which suggests that addictive drugs usurp common neural plasticity mechanisms that normally help form episodic memories to instead form addiction-related memories. Although this theory has been supported by the striking similarities between drug- induced cellular adaptations and experience-dependent neural plasticity, it falls short in explaining how addiction-related memories are extremely durable and resistant to extinction. Using cocaine as the drug model, we have begun to address this critical point over the past few years by hypothesizing that exposure to cocaine "wakes up" dormant, highly-efficient cellular mechanisms that are otherwise only present in the developing brain to profoundly reform specific neural circuits, resulting in extremely durable circuitry and behavioral alterations associated with addiction. This hypothesis was based on our initial observation (published in 2009) that exposure to cocaine generates a large number of silent excitatory synapses in the nucleus accumbens shell (NAc), an essential brain region for motivated behaviors. Silent synapses usually only contain NMDA receptors (NMDARs), with AMPA receptors (AMPARs) either absent or highly labile. Thus, these synapses are often "silent" at near resting membrane potentials. Abundant in the developing brain, many silent synapses are thought to be immature synaptic contacts; upon maturation by recruiting/stabilizing AMPARs, silent synapses may evolve into fully functional synapses to form new circuits. As such, the generation and potential maturation of silent synapses may be one of the critical developmental mechanisms that exposure to cocaine resumes to induce long-lasting circuitry and behavioral alterations. Among extensive excitatory synaptic inputs to the NAc, the afferents from the medial prefrontal cortex (mPFC) are particularly important for several core aspects of cocaine addiction including cocaine seeking and craving after withdrawal from cocaine self-administration (SA). Our current preliminary results show that silent synapses are generated within the mPFC-to-NAc pathway, and maturation of cocaine-generated silent synapses within this pathway is temporally correlated with the progressive intensification of cocaine seeking (incubation of cocaine craving). Using cocaine SA and seeking as the animal models, we will test the hypothesis that cocaine SA recruits developmental mechanisms to generate silent synapses within the mPFC-to-NAc pathway in the adult rat brain; maturation of these synapses during cocaine withdrawal and the resulting re-organization of the mPFC-to-NAc pathway critically contribute to withdrawal-associated cocaine craving and seeking. Expected outcomes of the proposed research will unveil novel molecular and cellular processes contributing to cocaine relapse and provide molecular targets for potential clinical treatment.