Cocaine Modulation of Synapses onto Dopamine Neurons

可卡因对多巴胺神经元突触的调节

• 批准号: 10197089
• 负责人: Jacques Wadiche
• 金额: $ 18.66万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10197089
• 关键词: AMPA Receptors; Address; Affect; Affinity; Attention; Biological Assay; Brain; Cells; Cocaine; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Data; Exhibits; Exposure to; Frequencies; Glutamates; Goals; Hour; Injections; Knowledge; Learning; Measures; Mediating; Midbrain structure; Mus; Pathology; Permeability; Pharmaceutical Preparations; Probability; Property; Proxy; Psychological reinforcement; Rewards; Role; Signal Transduction; Substantia nigra structure; Synapses; Synaptic Receptors; Synaptic Transmission; Synaptic plasticity; Testing; Training; Variant; Ventral Tegmental Area; Vesicle; addiction; base; biophysical properties; cocaine exposure; dopaminergic neuron; drug of abuse; drug reinforcement; drug seeking behavior; experimental study; follow-up; indexing; insight; neglect; novel; pars compacta; postsynaptic; presynaptic; quantum; receptor; two-photon; vesicular release; voltage

Abstract Identification of the mechanism(s) responsible for drug reinforcement is a key step in understanding the mechanism of reinforcement learning, but has so far proven elusive. The dopamine neurons of the ventral tegmental area and substantia nigra pars compacta, located within the ventral mesencephalon, are a central locus for drug reinforcement. Even a single exposure to cocaine is sufficient to alter synaptic transmission to dopamine neurons, with attention focused on postsynaptic mechanisms of plasticity mediated by AMPA receptors (AMPARs). Most AMPARs are impermeable to Ca2+ (CI-AMPAR) whereas receptors that lack the GluR2 subunit are permeable to Ca2+ (CP-AMPAR). A biophysical characteristic known as rectification is commonly used to differentiate CP-AMPARs from the more common CI-AMPARs . It is commonly accepted that cocaine exposure alters rectification of AMPAR synaptic currents on dopamine neurons without affecting measures of release probability, pointing to postsynaptic mechanisms of synaptic plasticity. However, our new data challenges the assumptions that rectification is sufficient to infer AMPAR subunit composition and that release probability is sufficient to assess presynaptic efficacy. Rather, our data shows that changes in the readily-releasable pool of vesicles can robustly alter presynaptic efficacy without a change in the release probability and that presynaptic mechanisms can affect rectification properties of AMPAR synaptic currents. Based on our data, we hypothesize that presynaptic mechanisms contribute to synaptic changes in dopamine neurons following cocaine exposure. We will first test AMPAR properties in dopamine neurons from naïve and cocaine-treated mice under conditions that isolate postsynaptic mechanisms. We will then follow up to test whether presynaptic changes contribute to synaptic plasticity induced by cocaine exposure. Presynaptic efficacy and AMPAR subunit composition have important functional consequences ranging from regulating the ability of postsynaptic cells to precisely follow high-frequency synaptic activity and mediating Ca2+ influx that can trigger plasticity or pathology like addiction. Successful completion of the proposed studies has potential to reveal novel mechanisms underlying synaptic plasticity at synapses onto dopamine neurons following exposure to drugs of abuse.

摘要 确定负责药物强化的机制是理解药物强化的关键步骤。 这是一种强化学习机制，但迄今为止被证明是难以捉摸的。腹侧的多巴胺神经元 位于中脑腹侧的被盖区和黑质部是中脑的中枢神经系统， 用于药物强化的位点。即使一次接触可卡因也足以改变突触传递， 多巴胺神经元，重点关注AMPA介导的突触后可塑性机制 受体（AMPAR）。大多数AMPAR对Ca 2+是不可渗透的（CI-AMPAR），而缺乏钙离子通道的受体则不能渗透。 GluR 2亚基对Ca ~（2+）具有渗透性（CP-AMPAR）。一种被称为整流的生物物理特征， 通常用于区分CP-AMPAR与更常见的CI-AMPAR。人们普遍认为高校 可卡因暴露改变了多巴胺神经元上AMPAR突触电流的整流， 释放概率的措施，指向突触可塑性的突触后机制。然而，我们的新 数据挑战了这样的假设：整流足以推断AMPAR亚基组成，并且 释放概率足以评估突触前功效。相反，我们的数据显示， 一个易于释放的囊泡池可以有力地改变突触前效应，而不改变释放 突触前机制可以影响AMPAR突触电流的整流特性。 根据我们的数据，我们假设突触前机制有助于突触的变化， 可卡因暴露后的多巴胺神经元我们将首先在多巴胺神经元中测试AMPAR特性 在分离突触后机制的条件下，从幼稚和可卡因处理的小鼠中分离。然后我们将 随访以测试突触前变化是否有助于可卡因暴露诱导的突触可塑性。 突触前效能和AMPAR亚基组成具有重要的功能后果， 调节突触后细胞精确跟踪高频突触活动的能力， Ca 2+内流可触发可塑性或病理学，如成瘾。成功完成拟议的研究 有可能揭示多巴胺神经元突触可塑性的新机制 在接触药物滥用后。

项目成果

Afferent convergence to a shared population of interneuron AMPA receptors.

• DOI: 10.1038/s41467-023-38854-2
• 发表时间: 2023-05-30
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Pennock, Reagan L.;Coddington, Luke T.;Yan, Xiaohui;Overstreet-Wadiche, Linda;Wadiche, Jacques I.
• 通讯作者: Wadiche, Jacques I.