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 治疗药物使用障碍（SUD）仍然是未满足的医疗需求，部分原因是其高复发率。在禁欲期间，重新暴露了以前与药物使用相关的提示触发强烈的药物渴望和寻求，从而导致药物复发。啮齿动物的研究表明，可卡因经验以可卡因的经验对谷氨酸前额叶皮层（IL）到伏伏核壳（NACSH）的谷氨酸能投射，以调节与提示相关的奖励寻求。 IL投影在NACSH内的主，中刺神经元（MSN）的两个亚型上形成了单突触连接，一种主要表达D1多巴胺受体和其他表达的D2受体。越来越多的证据表明，在可卡因自我给药后，IL-TO-D1与IL-D2亚项目经历了不同的适应性变化，并且有助于可卡因相关的行为。但是，是否通过修改现有突触而不改变基本电路连接性，或通过突触形成或消除来改变这些IL子项目的更改仍然很鲜为人知。当前提出的工作将通过重点关注可卡因生成的AMPA受体（AMPAR） - 丝状突触来解决这一知识差距，这是一种含有NMDA受体的一种谷氨酸能突触，没有功能稳定的AMPAR。无声突触可以通过突触发生生成，并在AMPAR插入和成熟后创建和稳定新的网络连接。相反，沉默的突触也可能源于通过AMPAR内在化的先前存在的突触，而这种初始的突触削弱可能会导致最终消除突触以减少网络连接。初步研究表明，可卡因自我给药在IL-D1和IL-D1和IL-D2亚注意中都产生了沉默的突触，该突触在解剖和功能上分别与突触发生相关，分别与突触相关。这些和其他结果导致了一个中心假设，即在可卡因撤离后，分别在IL-TO-D1和IL-D2亚弹射中同时诱导了沉默的突触介导的增强与弱化，并分别诱导了IL-DO-D2次介质，并且导致的电路重塑产生的电路重塑有助于提示诱导的可卡因寻求可卡因。 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)确定每种重塑的IL至nacsh子项目如何影响提示引起的可卡因寻求和动机，以便从可卡因退出后获得可卡因。这些目标与NIDA NIH的任务高度相关，因为结果结果将提供新颖的基于电路的机制，这些机制可以针对减少药物寻求和复发。