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.

抽象的 识别负责药物增强机制的机制是理解该机制的关键步骤 强化学习的机制，但迄今已证明弹性。腹侧的多巴胺神经元 位于腹腹膜脑内的细盖区域和底块nigra pars compacta是一个中央 药物加固的基因座。即使是一次接触可卡因也足以将突触传播改变为 多巴胺神经元，注意力集中在AMPA介导的可塑性后突触机制上 受体（AMPAR）。大多数AMPAR对Ca2+（Ci-Ampar）的不渗透，而缺乏的受体 GLUR2亚基可渗透到Ca2+（CP-Ampar）。一种称为纠正的生物物理特征是 通常用于区分CP-Ampars和更常见的CI-Ampars。通常被接受 可卡因暴露改变了多巴胺神经元上AMPAR突触电流的纠正而不会影响 释放概率的度量，指向突触可塑性的突触后机制。但是，我们的新人 数据挑战了纠正足以推断AMPAR亚基组成的假设，并且 释放概率足以评估突触前效率。相反，我们的数据显示了 容易发生的蔬菜池可以牢固地改变突触前的效率而不会改变释放 概率和突触前机制会影响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 在分离突触后机制的条件下，从幼稚和可卡因处理的小鼠中进行。然后我们会 跟进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。 突触前效率和AMPAR亚基组合物具有重要的功能后果 调节突触后细胞精确遵循高频突触活动和介导的能力 CA2+影响会引发可塑性或病理等病理等影响。成功完成拟议的研究 有可能揭示突触上突触可塑性的新型机制到多巴胺神经元上 暴露于滥用药物之后。

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.