NOVEL MODES OF ACTION OF ABUSED DRUGS

描述：申请人摘要 本申请寻求博士的5年研究生涯奖的续期。 菲利普·M格罗夫斯。 所提议的研究和多项合作将 进一步发展和扩展申请人关于新模式的知识 精神兴奋剂的作用。 几种安非他明引起的运动 重复给药可增强反应，这种现象称为 行为敏感化 多巴胺敏感性的变化 体树突和终末轴突自身受体可能有助于行为 致敏 实验提出使用终端兴奋性，在 突触前受体刺激的体内电生理测量 由申请人开发，与微透析结合，以提供 进一步研究多巴胺轴突突触前变化的有力工具 致敏大鼠终末。 最近的研究表明， 神经传导可能是发展中的关键， 致敏 兴奋性测量和透析将用于评估 基底神经元的突触前神经传入可能发生变化 神经节 此外，记录皮层神经元反应和纹状体神经元反应， 场电位从行为的动物将被用来研究的影响 对皮质纹状体传播的影响 计划进行合作 增强申请人对蛋白质表征技术的了解 该方法将用于研究安非他明的作用。 可能 据信，安非他明剂量递增所产生的神经毒性作用 模仿“暴饮暴食”将被调查。 在体细胞内记录 技术将检查冲动引起的持久 突触前皮质纹状体兴奋性和突触后 LTP或LTD的表达。使用 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回路。 的 申请人还将确定是否多巴胺能输入到棘上， 与来自特定皮层和丘脑区域的输入有关， 这些会聚模式对于被识别为 属于直接或间接输出途径。 丘脑输入 将表征参与这两种途径的多刺神经元。 一 超微结构研究的新领域将研究 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的种类， 确定它们的亚细胞位置，并检查 突触形成的多巴胺和丘脑传入的 胆碱能细胞

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.