Conditioned Cocaine Reward and Nucleus Accumbens Synaptic Plasticity

描述（由申请人提供）：持续易复发性是药物成瘾临床治疗的主要障碍。该提案的目标是了解控制药物寻求行为的神经机制，特别是在丘脑核（NAc）中的兴奋性突触可塑性。在成瘾的动物模型中，NAc谷氨酸传输已明确涉及寻求药物行为的消退和恢复。我们拟采用全细胞膜片钳电生理技术，在小鼠急性脑片上观察位置条件反射时，NAc兴奋性突触功能与条件可卡因奖赏消退和恢复的关系。我们的初步研究证明了这种方法的可行性，也支持NAc突触强度和恢复之间的关系。我们将使用位置条件反射范式的灵活性来研究药物寻求行为的减少（灭绝）和增加（恢复）。我们预测，恢复涉及减少NAc突触强度，并阻止这种减少将防止恢复行为。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-已知有助于灭绝的部分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制。研究结果将指导开发针对谷氨酸传输的治疗干预措施，以减少人类吸毒成瘾者复发的脆弱性。 公共卫生相关性：吸毒成瘾是一个主要的公共卫生问题，当以前的吸毒成瘾者再次吸毒时，这个问题就会持续下去。这项研究将帮助我们了解药物使用引起的大脑功能变化，这些变化使成瘾者容易复发。它还将研究如何改变大脑功能以减少对药物的追求。

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.