NMDA RECEPTOR REGULATION IN ADDICTION

NMDA 受体对成瘾的调节

• 批准号: 8275874
• 负责人: James A Bibb
• 金额: $ 31.77万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-15 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8275874
• 关键词: Acute; Adult; Attenuated; Behavior; Behavior Control; Behavioral Assay; Brain; Cell surface; Chronic; Cocaine; Cognition; Corpus striatum structure; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; DRD2 gene; Disease; Dopamine; Dopamine D1 Receptor; Dopamine Receptor; Drug Addiction; Environmental Risk Factor; Extinction (Psychology); Glutamates; Goals; Individual; Knock-out; Learning; Maintenance; Mediating; Memory; Molecular; Mus; N-Methyl-D-Aspartate Receptors; Neurobiology; Neurons; Nucleus Accumbens; Pathway interactions; Peptides; Pharmaceutical Preparations; Phosphorylation; Process; Protein Dephosphorylation; Protein Kinase; Protein Phosphatase 2A Regulatory Subunit PR53; Public Health; Regulation; Rewards; Role; Self Administration; Signal Pathway; Signal Transduction; Site; Sucrose; Surface; Synapses; Transgenic Organisms; Translational Research; Viral; Wild Type Mouse; Withdrawal; addiction; base; cocaine exposure; craving; drug of abuse; emotional factor; experience; motivated behavior; neuropsychiatry; neurotransmission; novel; receptor; recombinase; reward circuitry; therapy development; viral gene delivery

DESCRIPTION (provided by applicant): Drug addiction is a widespread and severe neuropsychiatric disorder and a major public health concern. It is characterized by loss of behavioral control as the neurobiological processes of learning and memory of information that motivates actions to acquire rewards are overwhelmed by the pharmacological effects of the drug. Combined with other environmental and emotional factors, motivated drug taking leads to compulsive craving, seeking, and taking that define addiction. Reward and addiction learning are mediated by molecular mechanisms of synaptic remodeling at dopaminergic and glutamatergic synapses. Identifying and validating these mechanisms is key to understanding addiction and developing effective strategies to treat it. We have discovered a new mechanism that mediates cognition through the regulation of NMDA receptors (NMDARs). This mechanism involves the modulation of the phosphorylation state of Ser1116 of the NR2B subunit of these receptors. This site is phosphorylated by the neuronal protein kinase, Cdk5. Cdk5 knockout (KO) or inhibition reduces phospho-Ser1116 NR2B, increases cell surface levels of the receptor, increases NMDAR-mediated current, and enhances cognition. Interestingly acute cocaine exposure, causes dephosphorylation of this site, likely facilitating reward learning. In contrast, chronic cocaine exposure potentiates this site, possibly attenuating further learning, thereby contributing to the perpetuation of the addicted state. We believe this mechanism provides a new avenue to understanding the molecular basis of addiction. We propose to study the regulation of this mechanism by cocaine and dopamine signal transduction. We will characterize its modulation during acquisition of self-administration (SA), chronic SA, and extinction after withdrawal from sucrose and cocaine SA in mice. We will define the effects of loss of Cdk5 and reduced phospho-Ser1116 NR2B on sucrose and cocaine SA by temporally and spatially controlled Cdk5 KO. Finally, we will specifically target and validate the role of this mechanism in acquisition, extinction, and reinstatement of sucrose and cocaine SA by viral gene delivery of novel drug-like small interfering peptides that disrupt NR2B-Cdk5 interactions. This translational research will significantly advance our understanding of the mechanisms of addiction and may contribute to the development of treatments to help addicted individuals recover. PUBLIC HEALTH RELEVANCE: Drug addiction is a major neuropsychiatric disorder caused by overstimulation of the brain's natural reward learning pathways, which mediate motivated behaviors. We have discovered a new and important molecular mechanism of synaptic remodeling that involves regulation of the NR2B subunit of NMDA receptors in the brain's reward circuitry that is targeted by cocaine. The goal of this project is to characterize the regulation of this reward learning mechanism, define its contribution to cocaine self-administration, and validate it as a potential target to enhance extinction of drug seeking and taking behavior, so that new treatments for addiction may be developed.

描述（由申请人提供）：吸毒成瘾是一种广泛且严重的神经精神疾病，也是一个主要的公共卫生问题。它的特点是行为控制的丧失，因为学习和记忆信息的神经生物学过程被药物的药理作用所淹没，而这些过程激发了获得奖励的行动。与其他环境和情感因素相结合，吸毒动机会导致强迫性的渴望、寻求和吸食，从而定义成瘾。奖励和成瘾学习是由多巴胺能和谷氨酸能突触的突触重塑的分子机制介导的。识别和验证这些机制是理解成瘾和制定有效治疗策略的关键。我们发现了一种通过调节 NMDA 受体（NMDAR）来介导认知的新机制。该机制涉及这些受体 NR2B 亚基 Ser1116 磷酸化状态的调节。该位点被神经元蛋白激酶 Cdk5 磷酸化。 Cdk5 敲除 (KO) 或抑制可减少磷酸化 Ser1116 NR2B，增加受体的细胞表面水平，增加 NMDAR 介导的电流，并增强认知能力。有趣的是，急性可卡因暴露会导致该位点去磷酸化，可能促进奖励学习。相反，长期接触可卡因会增强该部位，可能会削弱进一步的学习，从而导致成瘾状态的持续。我们相信这种机制为理解成瘾的分子基础提供了新途径。我们建议研究可卡因和多巴胺信号转导对该机制的调节。我们将描述其在小鼠获得自我给药 (SA)、慢性 SA 以及戒除蔗糖和可卡因 SA 后消退过程中的调节作用。我们将通过时间和空间控制的 Cdk5 KO 来定义 Cdk5 丢失和还原磷酸 Ser1116 NR2B 对蔗糖和可卡因 SA 的影响。最后，我们将具体针对并验证该机制在以下方面的作用： 通过病毒基因传递破坏 NR2B-Cdk5 相互作用的新型药物样小干扰肽来获取、消除和恢复蔗糖和可卡因 SA。这项转化研究将显着增进我们对成瘾机制的理解，并可能有助于开发帮助成瘾者康复的治疗方法。 公共健康相关性：药物成瘾是一种主要的神经精神疾病，是由于过度刺激大脑的自然奖励学习途径而引起的，该途径会介导动机行为。我们发现了一种新的重要的突触重塑分子机制，该机制涉及可卡因靶向的大脑奖赏回路中 NMDA 受体 NR2B 亚基的调节。该项目的目标是描述这种奖励学习机制的调节特征，定义其对可卡因自我给药的贡献，并验证其作为促进毒品寻求和吸毒行为消除的潜在目标，以便为成瘾提供新的治疗方法。发达。