NOVEL MODES OF ACTION OF ABUSED DRUGS

描述：申请者摘要 本申请寻求续签博士5年研究生涯奖。 菲利普·M·格罗夫斯。建议的研究和多项合作将 进一步发展和扩展申请者对新模式的知识 精神运动兴奋剂的作用。几种苯丙胺诱发的运动 通过重复给药来增强反应，这种现象被称为 行为敏感化。多巴胺敏感性的变化 躯体树突和终末轴突自身受体可能参与行为 敏化。提出了使用终端兴奋性的实验，一种 突触前受体刺激的在体电生理测量 由申请人开发，与微透析相结合以提供 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， 谷氨酸能传递可能在糖尿病的发生发展中起关键作用。 敏化。将使用兴奋性测量和透析来评估 谷氨酸能传入基底区可能的突触前改变 神经节。此外，皮层神经元反应和纹状体的记录 我们将利用动物行为产生的场势来研究这些效应。 安非他明对皮质纹状体传播的影响。计划开展协作 提高申请者对蛋白质鉴定技术的认识 这将被用于研究苯丙胺的作用。可能的 认为安非他明剂量递增会产生神经毒性作用 模仿“暴饮暴食”将被调查。活体细胞内记录 技术将检验冲动诱导的长期持续时间与 突触前皮质纹状体兴奋性和突触后的变化 LTP或LTD的表达。光学和电子显微镜研究使用 先进的标记方法和层析三维重建 将进一步阐明大脑皮层和新纹状体的回路。这个 申请者还将确定脊椎上的多巴胺能输入是否 与来自特定皮质和丘脑区域的输入相关联 这些收敛模式对于被识别为 属于直接或间接输出路径。丘脑输入到 我们将描述参与这两条通路的带刺神经元的特征。一个 超微结构研究的新领域将探讨 黑质纹状体多巴胺轴突上的非突触释放部位。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，并检查它们之间的关联 由多巴胺能和丘脑传入形成的突触 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.