Conditioned Cocaine Reward and Nucleus Accumbens Synaptic Plasticity

条件可卡因奖励和伏核突触可塑性

• 批准号: 7485301
• 负责人: Patrick Rothwell
• 金额: $ 2.62万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7485301
• 关键词: Acute; Agonist; Animal Model; Animals; Behavior; Brain; Cells; Chronic; Clinical Treatment; Cocaine; Condition; Cycloserine; Daily; Development; Drug Addiction; Drug Exposure; Drug Metabolic Detoxication; Drug usage; Electrophysiology (science); Extinction (Psychology); Glutamates; Goals; Human; Injection of therapeutic agent; Knowledge; Learning; Left; Mediating; Memory; Mus; N-Methyl-D-Aspartate Receptors; National Institute of Drug Abuse; Nature; Neuronal Plasticity; Nucleus Accumbens; Pharmaceutical Preparations; Physiological; Play; Pliability; Preparation; Public Health; Relapse; Research; Rewards; Role; Running; Signal Transduction; Slice; Synapses; Synaptic Transmission; Synaptic plasticity; Techniques; Testing; Therapeutic Intervention; Thinking; addiction; conditioning; desire; drug addict; drug addiction pharmacotherapy; drug of abuse; drug seeking behavior; experience; interest; neuroadaptation; neuromechanism; patch clamp; preference; prevent; research study; response; synaptic function; therapeutic target; transmission process

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.

描述（由申请人提供）：持续易复发是毒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，特别是伏隔核（NAc）的兴奋性突触可塑性。在成瘾动物模型中，NAc 谷氨酸传输显然与药物寻求行为的消失和恢复有关。我们建议使用全细胞膜片钳电生理学对小鼠的急性脑切片进行位置调节范式，以研究 NAc 中的兴奋性突触功能与条件性可卡因奖赏的消失和恢复之间的关系。我们的初步研究证明了这种方法的可行性，并且也支持 NAc 突触强度和恢复之间的关系。我们将利用场所条件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 NAc 突触强度的降低，并且阻止这种减少将阻止恢复行为。相反，我们预计灭绝会增强 NAc 突触强度，并且当动物给予 D-环丝氨酸（一种已知可促进灭绝的部分 NMDA 受体激动剂）时，这种变化将会加速。这些实验为研究突触可塑性和行为之间的关系提供了一个独特的机会，在突触可塑性和行为都可以双向调节的情况下。研究结果将指导针对谷氨酸传输的治疗干预措施的开发，从而降低人类吸毒成瘾者复发的可能性。 公共卫生相关性：吸毒成瘾是一个重大的公共卫生问题，当以前的吸毒者再次吸毒时，这一问题就会持续存在。这项研究将帮助我们了解吸毒引起的大脑功能变化，这些变化使吸毒者容易复吸。它还将研究如何改变大脑功能以减少对毒品的追求。