NMDA RECEPTOR REGULATION IN ADDICTION

NMDA 受体对成瘾的调节

• 批准号: 9059685
• 负责人: James A Bibb
• 金额: $ 13.19万
• 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 2016-10-05
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9059685
• 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; 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; glutamatergic signaling; memory consolidation; motivated behavior; neuropsychiatric disorder; neurotransmission; novel; novel therapeutics; 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，也是一个主要的公共卫生问题。它的特点是失去行为控制，因为神经生物学过程的学习和记忆的信息，激励行动，以获得奖励被药物的药理作用压倒。再加上其他环境和情感因素，有动机的吸毒会导致强迫性的渴望、寻求和服用，这就是成瘾的定义。多巴胺能和谷氨酸能突触突触重塑的分子机制介导了奖励和成瘾学习。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。该机制涉及这些受体NR2B亚基的Ser1116磷酸化状态的调节。这个位点被神经元蛋白激酶Cdk5磷酸化。Cdk5敲除（KO）或抑制可降低phospho-Ser1116 NR2B，增加受体的细胞表面水平，增加nmda介导的电流，并增强认知。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这个部位，可能会减弱进一步的学习，从而导致成瘾状态的延续。我们相信这种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。我们将描述其在小鼠自我给药（SA）的获得、慢性SA以及从蔗糖和可卡因中退出SA后的消失过程中的调节。我们将通过时间和空间控制Cdk5 KO来确定Cdk5缺失和磷酸化ser1116 NR2B减少对蔗糖和可卡因SA的影响。最后，我们将具体针对并验证该机制在