NMDA RECEPTOR REGULATION IN ADDICTION

描述(申请人提供)：毒瘾是一种广泛和严重的神经精神障碍，是一个主要的公共卫生问题。它的特征是行为控制的丧失，因为药物的药理效应压倒了学习和记忆信息的神经生物学过程，这些过程激励着获得奖励的行动。与其他环境和情感因素相结合，动机吸毒会导致强迫性渴望、寻求和服用，这是成瘾的定义。奖赏和成瘾学习是由多巴胺能和谷氨酸能突触重塑的分子机制介导的。识别和验证这些机制是了解成瘾和制定有效的治疗策略的关键。我们发现了一种通过调节NMDAR(NMDARs)来调节认知的新机制。这一机制涉及这些受体的NR2B亚单位Ser1116的磷酸化状态的调节。这个位点被神经元蛋白激酶CDK5磷酸化。CDK5基因敲除(KO)或抑制降低了磷酸化的Ser1116NR2B，增加了细胞表面受体的水平，增加了NMDAR介导的电流，并增强了认知。有趣的是，急性可卡因暴露会导致这个部位的去磷酸化，可能会促进奖赏学习。相比之下，长期接触可卡因会增强这一部位，可能会削弱进一步的学习，从而导致成瘾状态的持久存在。我们相信这一机制为理解成瘾的分子基础提供了一条新的途径。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。我们将描述它在小鼠获得自我给药(SA)、慢性SA以及停用蔗糖和可卡因SA后消退的过程中的调节特征。我们将通过时间和空间控制的CDK5 KO来确定CDK5的丢失和还原的磷酸化Ser1116NR2B对蔗糖和可卡因SA的影响。最后，我们将具体针对和验证这一机制在 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得、消除和恢复蔗糖和可卡因SA。这项翻译研究将极大地促进我们对成瘾机制的理解，并可能有助于开发帮助成瘾患者康复的治疗方法。

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.