NOVEL MODES OF ACTION OF ABUSED DRUGS

滥用药物的新作用模式

• 批准号: 6174490
• 负责人: PHILIP M GROVES
• 金额: $ 11.37万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-09-30 至 2003-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6174490
• 关键词: amphetamines; basal ganglia; behavioral habituation /sensitization; brain mapping; dopamine agonists; dopamine antagonists; dopamine receptor; drug abuse; drug metabolism; electron microscopy; electrophysiology; glutamates; laboratory rat; microdialysis; neural transmission; neuroanatomy; neurotoxins; pharmacokinetics; psychotropic drugs; synapses; thalamus

DESCRIPTION: Applicant's Abstract This application seeks renewal of a 5 year Research Career Award for Dr. Philip M. Groves. The research and multiple collaborations proposed will further develop and extend the applicant's knowledge about the novel modes of action of psychomotor stimulants. Several amphetamine-induced motor responses are enhanced by repeated administration, a phenomenon termed behavioral sensitization. Changes in the sensitivity of dopamine somatodendritic and terminal axon autoreceptors may contribute to behavioral sensitization. Experiments are proposed using terminal excitability, an in vivo electrophysiological measure of presynaptic receptor stimulation developed by the applicant, in combination with microdialysis to provide a powerful tool for further study of presynaptic changes in the dopamine axon terminal in sensitized rats. Recent studies indicate that alterations in glutamatergic transmission may be critical in the development of sensitization. Excitability measures and dialysis will be used to assess possible presynaptic changes in glutamatergic afferents to the basal ganglia. In addition, recordings of cortical neuron responses and striatal field potentials from behaving animals will be employed to study the effects of amphetamine on corticostriatal transmission. A collaboration is planned to enhance the applicant's knowledge of protein characterization techniques which will be applied to study the effects of amphetamine. Possible neurotoxic effects produced by escalating amphetamine dose regimens believed to mimic "bingeing" will be investigated. In vivo intracellular recording techniques will examine the relation between impulse-induced long-lasting changes in presynaptic corticostriatal excitability and post-synaptic expressions of LTP or LTD. Light and electron microscope studies using advanced labeling methods and tomographic three-dimensional reconstruction will further elucidate the circuitry of the cortex and neostriatum. The applicant will also determine whether dopaminergic inputs onto spines are associated with inputs from specific cortical and thalamic regions and if these patterns of convergence differ for spiny neurons identified as belonging to the direct or indirect output pathways. Thalamic input onto spiny neurons participating in the two pathways will be characterized. A new area of ultrastructural research will examine the possibility of nonsynaptic release sites on nigrostriatal dopamine axons. Electron microscopic evidence will also be sought for the presence of D1 and D2 classes of dopamine receptors on striatal cholinergic interneurons, to identify their subcellular locations, and to examine the association of synapses formed by the dopaminergic and thalamic afferents to the cholinergic cells.

描述：申请人的摘要 本申请旨在为 Dr. 续签 5 年研究职业奖。 菲利普·M·格罗夫斯. 拟议的研究和多项合作将 进一步发展和扩展申请人对新颖模式的了解 精神运动兴奋剂的作用。 几种安非他明诱发的运动 重复给药可以增强反应，这种现象被称为 行为敏化。 多巴胺敏感性的变化 体细胞树突和末端轴突自身受体可能有助于行为 敏化。 实验建议使用终端兴奋性，一种in 突触前受体刺激的体内电生理测量 由申请人开发，与微透析相结合，提供 进一步研究多巴胺轴突突触前变化的有力工具 致敏大鼠的终末期。 最近的研究表明，改变 谷氨酸能传递可能在发育中至关重要 敏化。 将使用兴奋性测量和透析来评估 谷氨酸能传入基底细胞可能发生突触前变化 神经节。 此外，皮质神经元反应和纹状体的记录 将利用行为动物的场电位来研究其影响 安非他明对皮质纹状体传递的影响。 已计划合作 增强申请人对蛋白质表征技术的了解 它将用于研究安非他明的作用。 可能的 据认为，增加安非他明剂量方案会产生神经毒性作用 模仿“暴饮暴食”的行为将受到调查。 体内细胞内记录 技术将检查冲动引起的持久之间的关系 突触前皮质纹状体兴奋性和突触后的变化 LTP 或 LTD 的表达式。 使用光学和电子显微镜研究 先进的标记方法和断层扫描三维重建 将进一步阐明皮层和新纹状体的电路。 这 申请人还将确定刺上的多巴胺能输入是否是 与特定皮质和丘脑区域的输入相关，如果 这些收敛模式对于被识别为的多刺神经元来说是不同的 属于直接或间接输出途径。 丘脑输入到 参与这两条通路的棘神经元将被表征。 一个 超微结构研究的新领域将检验以下可能性 黑质纹状体多巴胺轴突上的非突触释放位点。 电子 还将寻找 D1 和 D2 存在的微观证据 纹状体胆碱能中间神经元上的多巴胺受体类别 确定它们的亚细胞位置，并检查它们的关联 由多巴胺能和丘脑传入神经形成的突触 胆碱能细胞。