Synaptic Reorganization in Drug Addiction

描述（由申请人提供）：可卡因成瘾仍然是一个严重的医疗和社会问题。神经适应理论是药物成瘾的分子和细胞研究的一个重要指导性假设，它表明成瘾药物篡夺了通常有助于形成情景记忆的常见神经可塑性机制，从而形成成瘾相关记忆。虽然这一理论得到了药物诱导的细胞适应性和经验依赖的神经可塑性之间惊人相似性的支持，但它福尔斯在解释与成瘾有关的记忆是如何极其持久和抵抗消失方面做得不够。使用可卡因作为药物模型，我们已经开始解决这个关键点，在过去的几年里，通过假设暴露于可卡因“唤醒”休眠，高效的细胞机制，否则只存在于发育中的大脑中，以深刻改革特定的神经回路，导致极其持久的回路和行为。 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），即暴露于可卡因会在神经核壳（NAc）中产生大量沉默的兴奋性突触，这是动机行为的重要大脑区域。沉默突触通常只含有NMDA受体（NMDAR），AMPA受体（AMPAR）要么不存在，要么高度不稳定。因此，这些突触在接近静息膜电位时通常是“沉默的”。在发育中的大脑中大量存在，许多沉默的突触被认为是不成熟的突触接触;在通过招募/稳定AMPAR而成熟时，沉默的突触可以进化成完全功能的突触以形成新的回路。因此，沉默突触的产生和潜在成熟可能是暴露于可卡因恢复以诱导持久的电路和行为改变的关键发育机制之一。在广泛的兴奋性突触输入NAc，传入内侧前额叶皮层（mPFC）是特别重要的几个核心方面的可卡因成瘾，包括可卡因寻求和渴望后，从可卡因自我管理（SA）撤出。我们目前的初步结果表明，沉默的突触内产生的mPFC-NAc的途径，成熟的可卡因产生的沉默突触在这条途径与可卡因寻求（可卡因渴望的孵化）的逐步加强时间相关。使用可卡因SA和寻求的动物模型，我们将测试的假设，可卡因SA招聘的发展机制，以产生沉默的突触内的mPFC-NAc通路在成年大鼠大脑中，这些突触的成熟可卡因戒断过程中，并由此产生的重组mPFC-NAc通路的关键有助于戒断相关的可卡因的渴望和寻求。拟议研究的预期成果将揭示有助于可卡因复吸的新分子和细胞过程，并为潜在的临床治疗提供分子靶点。

DESCRIPTION (provided by applicant): 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.