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: 10041862
• 负责人: Jacques Wadiche
• 金额: $ 23.59万
• 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 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10041862
• 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.

抽象的 识别负责药物强化的机制是理解药物强化的关键一步 强化学习机制，但迄今为止被证明难以捉摸。腹侧多巴胺神经元 被盖区和黑质致密部位于腹侧中脑内，是中枢神经系统。 药物强化位点。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 不能渗透 Ca2+ (CI-AMPAR)，而缺乏 Ca2+ 的受体 GluR2 亚基可渗透 Ca2+ (CP-AMPAR)。称为整流的生物物理特征是 通常用于区分 CP-AMPAR 和更常见的 CI-AMPAR。这是普遍接受的 可卡因暴露会改变多巴胺神经元 AMPAR 突触电流的整流，但不影响 释放概率的测量，指出突触可塑性的突触后机制。然而，我们的新 数据挑战了以下假设：校正足以推断 AMPAR 亚基组成，并且 释放概率足以评估突触前功效。相反，我们的数据表明， 易于释放的囊泡池可以在不改变释放的情况下强烈改变突触前功效 概率以及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变化 可卡因暴露后的多巴胺神经元。我们将首先测试多巴胺神经元中的 AMPAR 特性 在隔离突触后机制的条件下，来自幼稚小鼠和可卡因治疗的小鼠。我们随后将 随访以测试突触前变化是否有助于可卡因暴露引起的突触可塑性。 突触前功效和 AMPAR 亚基组成具有重要的功能后果，包括： 调节突触后细胞精确跟随高频突触活动和介导的能力 Ca2+ 流入会引发可塑性或成瘾等病理现象。成功完成拟议的研究 有潜力揭示多巴胺神经元突触可塑性的新机制 接触滥用药物后。