Conditioned Cocaine Reward and Nucleus Accumbens Synaptic Plasticity

描述（由申请人提供）：持续易复发是药物成瘾临床治疗的主要障碍。本研究的目的是了解控制药物寻找行为的神经机制，特别是伏隔核（NAc）的兴奋性突触可塑性。在成瘾的动物模型中，NAc谷氨酸传递明显与药物寻求行为的消失和恢复有关。我们拟采用全细胞膜片钳电生理学方法对小鼠急性脑切片进行位置条件反射，研究NAc兴奋性突触功能与条理性可卡因奖励的消退和恢复之间的关系。我们的初步研究证明了这种方法的可行性，也支持了NAc突触强度与恢复之间的关系。我们将使用场所条件反射范式的灵活性来研究药物寻求行为的减少（消失）和增加（恢复）。我们预测恢复涉及NAc突触强度的降低，阻断这种降低将阻止恢复行为。相反，我们预计灭绝将增强NAc突触强度，当动物被给予d -环丝氨酸时，这种变化将加速，d -环丝氨酸是一种已知的促进灭绝的部分NMDA受体激动剂。这些实验提供了一个独特的机会来研究突触可塑性和行为之间的关系，在这种情况下，每一个都可以双向调节。这些结果将指导针对谷氨酸传递的治疗干预措施的发展，从而减少人类吸毒成瘾者复发的脆弱性。

DESCRIPTION (provided by applicant): Persistent vulnerability to relapse is a major obstacle in the clinical treatment of drug addiction. The goal of this proposal is to understand the neural mechanisms that control drug-seeking behavior, with specific reference to excitatory synaptic plasticity in the nucleus accumbens (NAc). In animal models of addiction, NAc glutamate transmission has been clearly implicated in both extinction and reinstatement of drug seeking behavior. We propose to use whole-cell patch-clamp electrophysiology in acute brain slices from mice run through a place conditioning paradigm, to study the relationship between excitatory synaptic function in NAc and the extinction and reinstatement of conditioned cocaine reward. Our preliminary studies demonstrate the feasibility of this approach, and also support a relationship between NAc synaptic strength and reinstatement. We will use the flexibility of the place conditioning paradigm to study both decreases (extinction) and increases (reinstatement) in drug-seeking behavior. We predict that reinstatement involves reduced NAc synaptic strength, and that blocking this reduction will prevent reinstatement behavior. Conversely, we expect that extinction will enhance NAc synaptic strength, and this change will be accelerated when animals are given D-cycloserine - a partial NMDA receptor agonist known to facilitate extinction. These experiments present a unique opportunity to study the relationship between synaptic plasticity and behavior in a situation where each can be-bidirectionally modulated. The results will guide the development of therapeutic interventions targeted at glutamate transmission that can reduce vulnerability to relapse in human drug addicts. PUBLIC HEALTH RELEVANCE: Drug addiction is a major public health problem that is perpetuated when former drug addicts relapse to using drugs again. This research will help us understand changes in brain function caused by drug use that leave addicts vulnerable to relapse. It will also examine how brain function might be modified to reduce the pursuit of drugs.