Synaptic Reorganization in Drug Addiction

描述(申请人提供)：可卡因成瘾仍然是一个严重的医学和社会问题。对药物成瘾的分子和细胞研究的一个重要的指导性假说是神经适应理论，该理论认为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，而形成了与成瘾相关的记忆。尽管这一理论得到了药物诱导的细胞适应和经验依赖的神经可塑性之间惊人的相似之处的支持，但它无法解释与成瘾相关的记忆是如何极其持久和抵抗消亡的。使用可卡因作为药物模型，我们在过去的几年里已经开始解决这个临界点，通过假设暴露在可卡因中“唤醒”休眠的、高效的细胞机制，否则这些机制只存在于发育中的大脑中，以深刻地改革特定的神经回路，导致极其持久的电路和行为 与上瘾有关的改变。这一假说是基于我们最初的观察结果(发表于2009年)，即暴露在可卡因中会在伏隔核壳(NAC)产生大量无声的兴奋性突触，NAC是动机行为的关键大脑区域。沉默的突触通常只含有NMDAR(NMDAR)，而AMPA受体(AMPAR)要么缺失，要么高度不稳定。因此，这些突触在接近静息的膜电位时通常是“沉默的”。在发育中的大脑中，许多沉默的突触被认为是不成熟的突触联系；当通过招募/稳定AMPAR而成熟时，沉默的突触可能进化成功能完备的突触，形成新的回路。因此，沉默突触的产生和潜在的成熟可能是恢复暴露于可卡因导致长时间回路和行为改变的关键发育机制之一。在广泛的兴奋性突触传入NAC中，来自内侧前额叶皮质(MPFC)的传入在可卡因成瘾的几个核心方面尤其重要，包括可卡因寻求和戒断后对可卡因的渴望。我们目前的初步结果表明，沉默突触是在mPFC-NAC途径中产生的，而在这一途径中由可卡因产生的沉默突触的成熟与可卡因寻求的逐渐加剧(可卡因渴望的孵化)在时间上是相关的。以可卡因SA和Seeking作为动物模型，我们将检验这一假说，即可卡因SA招募发育机制，在成年大鼠大脑中的mPFC-NAC通路中产生沉默突触；在可卡因戒断过程中，这些突触的成熟以及由此导致的mPFC-NAC通路的重组，对与戒断相关的可卡因的渴望和寻找起关键作用。拟议研究的预期结果将揭示导致可卡因复发的新的分子和细胞过程，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.