NMDA RECEPTOR REGULATION IN ADDICTION

NMDA 受体对成瘾的调节

• 批准号: 8652966
• 负责人: James A Bibb
• 金额: $ 31.8万
• 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/8652966
• 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.

描述（由申请人提供）：药物成瘾是一种广泛和严重的神经精神疾病，是一个主要的公共卫生问题。它的特征是行为控制的丧失，因为刺激行为以获得奖励的信息的学习和记忆的神经生物学过程被药物的药理作用所淹没。结合其他环境和情感因素，有动机的吸毒导致强迫性渴望，寻求和服用，定义成瘾。奖赏和成瘾学习是通过多巴胺能和多巴胺能突触的突触重构的分子机制介导的。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（NMDARs）介导认知的新机制。该机制涉及调节这些受体的NR 2B亚基的Ser 1116的磷酸化状态。该位点被神经元蛋白激酶Cdk 5磷酸化。Cdk 5敲除（KO）或抑制减少磷酸-Ser 1116 NR 2B，增加受体的细胞表面水平，增加NMDAR介导的电流，并增强认知。有趣的是，急性可卡因暴露导致该位点去磷酸化，可能促进奖励学习。相比之下，长期接触可卡因会增强这个部位，可能会减弱进一步的学习，从而有助于成瘾状态的持续。我们相信这一机制为理解成瘾的分子基础提供了新的途径。我们建议研究可卡因和多巴胺信号转导对这一机制的调节。我们将描述其调制过程中收购的自我管理（SA），慢性SA，并退出后，从蔗糖和可卡因SA小鼠的灭绝。我们将定义的影响损失的Cdk 5和减少磷酸丝氨酸1116 NR 2B蔗糖和可卡因SA的时间和空间控制Cdk 5 KO。最后，我们将具体针对并验证该机制在以下方面的作用： 通过病毒基因递送破坏NR 2B-Cdk 5相互作用的新型药物样小干扰肽，获得、消除和恢复蔗糖和可卡因SA。这项转化研究将大大推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。