Synaptic Actions of Amphetamine in the Striatum

安非他明在纹状体中的突触作用

• 批准号: 10668662
• 负责人: STEPHEN RAYPORT
• 金额: $ 56.21万
• 依托单位: NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10668662
• 关键词: Acute; Affect; Amphetamines; Anterior; Attenuated; Automobile Driving; Behavior; Behavioral; Cell membrane; Complex; Corpus striatum structure; Dopamine; Dopamine D1 Receptor; Dopamine D2 Receptor; Dopamine Receptor; Dorsal; Dose; Drug Addiction; Genetic Marker Expression; Glutamates; Heterogeneity; Hour; Interneurons; Lateral; Maps; Medial; Mediating; Membrane Transport Proteins; Metabotropic Glutamate Receptors; Neurons; Nucleus Accumbens; Pharmaceutical Preparations; Pharmacotherapy; Site; Synapses; Synaptic Transmission; Time; addiction; attenuation; cholinergic; dopaminergic neuron; drug action; gamma-Aminobutyric Acid; insight; neurotransmission; novel; postsynaptic; presynaptic; psychostimulant; putamen; receptor; therapeutic target; transmission process; uptake

Project summary Addictive psychostimulants such as amphetamine act at dopamine synapses in the striatum. Presynaptic amphetamine action drives dopamine release via activity-dependent and activity-independent mechanisms. Dopamine acts on multiple dopamine receptors that are differentially distributed on striatal neurons. Beyond this volume transmission, dopamine neurons engage in synaptic transmission that is operative on a fast time scale, compared to volume transmission, and involves not only dopamine, but also GABA and glutamate. This project focuses on these synaptic connections as a novel substrate for psychostimulant action. The synaptic transmission exerts excitatory effects through dopamine D1 receptors, ionotropic and metabotropic glutamate receptors, and inhibitory effects through dopamine D2 receptors and GABAA receptors. While dopaminergic and GABAergic synaptic connections are widespread, glutamatergic connections are concentrated in the medial nucleus accumbens and the anterior lateral dorsal striatum. Synaptic connections to cholinergic interneurons are the strongest, most complex, involving dopamine, GABA and glutamate. Remarkably glutamate cotransmission is abrogated by amphetamine administration, and abrogation of glutamate cotransmission attenuates psychostimulant responsiveness. The guiding hypothesis is that amphetamine- induced plasticity of a subset of dopamine neuron synapses is critical for driving the striatal circuitry towards the addicted state, particularly dopamine neuron synapses distinguished by glutamate cotransmission. The three specific aims are to: <1> Determine quantitatively amphetamine-induced plasticity of dopamine neuron synaptic connections to cholinergic interneurons in striatal subregions identified by synaptic connectivity-based clustering. <2> Determine direct synaptic effects of amphetamine on dopamine neuron synaptic transmission in striatal subregions distinguished by glutamate cotransmission. <3> Determine amphetamine effects on dopamine neuron terminal activity during amphetamine-induced behaviors. This project will advance understanding of the synaptic substrate of amphetamine action in the striatum, revealing loci of drug-induced plasticity that will inform the pharmacotherapy of addiction.

项目概要 安非他明等成瘾性精神兴奋剂作用于纹状体的多巴胺突触。突触前 安非他明作用通过活动依赖性和活动无关机制驱动多巴胺释放。 多巴胺作用于纹状体神经元上不同分布的多种多巴胺受体。超过 在这种体积传输中，多巴胺神经元参与快速运作的突触传输 与体积传输相比，规模传输不仅涉及多巴胺，还涉及 GABA 和谷氨酸。这 该项目的重点是这些突触连接作为精神刺激作用的新基质。突触 传输通过多巴胺 D1 受体、离子型和代谢型谷氨酸发挥兴奋作用 受体，以及通过多巴胺 D2 受体和 GABAA 受体的抑制作用。虽然多巴胺能 GABA能突触连接广泛存在，谷氨酸能连接集中在 内侧伏隔核和前外侧背侧纹状体。突触与胆碱能的连接 中间神经元是最强、最复杂的，涉及多巴胺、GABA 和谷氨酸。值得注意的是 服用安非他明可消除谷氨酸共传递，并且消除谷氨酸 共传递减弱了精神刺激的反应性。指导性假设是安非他明- 多巴胺神经元突触子集的诱导可塑性对于驱动纹状体电路走向至关重要 成瘾状态，特别是以谷氨酸共传递为特征的多巴胺神经元突触。这 三个具体目标是： <1> 定量测定安非他明诱导的多巴胺神经元的可塑性 基于突触连接识别的纹状体亚区与胆碱能中间神经元的突触连接 聚类。 <2> 测定安非他明对多巴胺神经元突触传递的直接突触作用 在纹状体次区域中，以谷氨酸共同传递为特征。 <3> 确定安非他明对 安非他明诱导行为期间多巴胺神经元末端活动。该项目将推进 了解纹状体中苯丙胺作用的突触底物，揭示药物诱导的位点 可塑性将为成瘾药物治疗提供信息。