Cocaine-induced adaptation in NMDA receptors

可卡因诱导的 NMDA 受体适应

• 批准号: 10472185
• 负责人: Yan Dong
• 金额: $ 44.43万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-01 至 2027-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10472185
• 关键词: AMPA Receptors; Address; Anatomy; Behavior; Behavioral; Behavioral inhibition; Cocaine; Cocaine withdrawal; Cues; Dendritic Spines; Dopamine D1 Receptor; Dopamine D2 Receptor; Drug usage; Electrophysiology (science); Exhibits; Exposure to; Generations; Glutamates; Human; Image; Knowledge; Mediating; Medical; Memory; Mission; Modeling; Modification; Molecular; Motivation; N-Methyl-D-Aspartate Receptors; National Institute of Drug Abuse; Neurons; Nucleus Accumbens; Pattern; Performance; Pharmaceutical Preparations; Prefrontal Cortex; Relapse; Research; Rewards; Rodent; Role; Source; Specificity; Structure; Substance Use Disorder; Synapses; Testing; Transgenic Mice; United States National Institutes of Health; Vertebral column; Work; cell type; cocaine related behaviors; cocaine seeking; cocaine self-administration; drug abstinence; drug craving; drug relapse; drug withdrawal; experience; experimental study; in vivo; in vivo imaging; novel; optogenetics; postsynaptic; prevent; receptor internalization; recruit; stem; synaptogenesis; tool

Abstract Treating substance use disorder (SUD) remains an unmet medical need, in part, due to its high relapse rate. During drug abstinence, re-exposure to cues previously associated with drug use triggers robust drug craving and seeking, leading to drug relapse. Rodent studies reveal that the glutamatergic projection from the infralimbic prefrontal cortex (IL) to nucleus accumbens shell (NAcSh) is targeted by cocaine experience to regulate cue-associated reward seeking. IL projections form monosynaptic connections on both of the two subtypes of principal, medium spiny neurons (MSNs) within the NAcSh, one predominantly expressing D1 dopamine receptors and the other expressing D2 receptors. Increasing evidence suggests that the IL-to-D1 vs. IL-to-D2 sub-projections undergo different adaptive changes after cocaine self-administration and differentially contribute to cocaine-associated behaviors. However, it remains poorly understood whether these IL sub-projections are changed through modification of existing synapses without changing the basic circuit connectivity, or through synapse formation or elimination that results in profound rewiring of circuit connectivity. The currently proposed work will address this knowledge gap by focusing on cocaine-generated AMPA receptor (AMPAR)-silent synapses, a type of glutamatergic synapses that contains NMDA receptors without functionally stable AMPARs. Silent synapses can be generated de novo via synaptogenesis and, upon AMPAR insertion and maturation, create and stabilize new network connections. Conversely, silent synapses can also stem from pre-existing synapses through AMPAR internalization, and this initial synaptic weakening may lead to the eventual synapse elimination to reduce network connections. Preliminary studies reveal that cocaine self-administration generated silent synapses in both the IL-to-D1 and IL-to-D2 sub-projections, which anatomically and functionally correlated with synaptogenesis vs. synaptic weakening, respectively. These and other results lead to the central hypothesis that silent synapse-mediated strengthening vs. weakening are simultaneously induced within the IL-to-D1 and IL-to-D2 sub-projections, respectively, after cocaine withdrawal, and the resulting circuit remodeling differentially contributes to cue-induced cocaine seeking. To test this hypothesis, the proposed experiments will (1) characterize the anatomical and electrophysiological consequences of silent synapse-mediated remodeling of IL-to-D1 and IL-to-D2 sub-projections, (2) determine the role of each of the remodeled IL-to-NAcSh sub-projections in formation of neuronal ensembles that potentially encode cue-induced cocaine seeking, and (3) determine how each of the remodeled IL-to-NAcSh sub-projections influences cue-induced cocaine seeking and motivation to obtain cocaine after withdrawal from cocaine. These objectives are highly relevant to the mission of the NIDA, NIH, as the resulting findings will provide novel, circuit-based mechanisms that can be targeted to reduce drug seeking and relapse.

抽象的 治疗物质使用障碍（SUD）仍然是一个未得到满足的医疗需求，部分原因是其高复发率。在戒毒期间，重新接触以前与吸毒相关的线索会引发强烈的药物渴望和寻求，导致药物复发。啮齿动物研究表明，可卡因体验的目标是从边缘下前额皮质（IL）到伏隔核壳（NAcSh）的谷氨酸能投射来调节与提示相关的奖励寻求。 IL 投射在 NAcSh 内主要中型棘神经元 (MSN) 的两种亚型上形成单突触连接，一种主要表达 D1 多巴胺受体，另一种主要表达 D2 受体。越来越多的证据表明，IL-to-D1 与 IL-to-D2 子预测在可卡因自我给药后经历了不同的适应性变化，并对可卡因相关行为产生了不同的影响。然而，人们对这些 IL 子投影是否是通过修改现有突触而不改变基本电路连接而改变，还是通过突触形成或消除而导致电路连接的深刻重新布线仍然知之甚少。目前提出的工作将通过关注可卡因生成的 AMPA 受体（AMPAR）沉默突触来解决这一知识差距，这是一种谷氨酸能突触，包含 NMDA 受体，但没有功能稳定的 AMPAR。沉默突触可以通过突触发生从头产生，并且在 AMPAR 插入和成熟后，创建并稳定新的网络连接。相反，沉默突触也可以通过 AMPAR 内化源自预先存在的突触，这种最初的突触减弱可能导致最终的突触消除，从而减少网络连接。初步研究表明，可卡因自我给药会在 IL-to-D1 和 IL-to-D2 子投影中产生沉默突触，这在解剖学和功能上分别与突触发生和突触减弱相关。这些和其他结果得出了一个中心假设，即在可卡因戒断后，分别在 IL-to-D1 和 IL-to-D2 子投影内同时诱导沉默突触介导的增强与减弱，以及由此产生的不同的回路重塑有助于提示诱导的可卡因寻找。为了检验这一假设，所提出的实验将（1）表征沉默突触介导的 IL-to-D1 和 IL-to-D2 子投影重塑的解剖学和电生理学后果，（2）确定每个重构的 IL-to-NAcSh 子投影形成神经元群，可能编码提示诱导的可卡因寻找，以及 (3) 确定每个重构的 IL-to-NAcSh 如何子预测影响线索诱导的可卡因寻求和戒除可卡因后获取可卡因的动机。这些目标与 NIDA、NIH 的使命高度相关，因为由此产生的发现将提供新颖的、基于回路的机制，可以有针对性地减少药物寻求和复发。