MECHANISM OF ACTION OF DRUGS OF ABUSE--AMPHETAMINE

描述：（改编自申请人摘要）本申请寻求更新研究支持，以继续研究精神运动兴奋剂的作用部位和机制。其总体目的是研究安非他明对纹状体谷氨酸和多巴胺神经传递的影响，以及与不同新纹状体输出细胞相关的谷氨酸和多巴胺轴突终止位点。具体来说，它将解决与全身性安非他明影响相关的三个问题：促成与成瘾相关的新纹状体变化的突触前机制，以及导致安非他明诱导的纹状体直接输出通路神经元活动增加的电路。这些药物的运动效应取决于它们增加多巴胺（DA）传递的能力。反复服用安非他明可增强几种运动反应；这种现象被称为行为敏感化。DA体树突和末端轴突自受体的敏感性变化可能与行为致敏有关。本实验拟采用突触前受体刺激的体内电生理指标——终兴奋性和微透析，进一步研究致敏大鼠黑纹状体DA轴突终突触前变化的基础。伏隔核和前额叶皮层的DA终端也将被检查。谷氨酸传递的改变也可能是致敏的关键。兴奋性测量将评估新纹状体、伏隔核和腹侧被盖区的谷氨酸能传入可能的突触前变化。其他研究将探讨冲动诱导的突触前皮质纹状体兴奋性的持久变化与突触后长期增强或抑郁的表达之间的关系。电镜研究将进一步阐明涉及DA和谷氨酸传入系统的新纹状体回路。将确定棘状树突上的DA输入是否与特定皮层和丘脑区域的输入有关，以及这些收敛模式是否在棘状神经元中属于直接和间接输出途径。丘脑是纹状体的主要兴奋性输入，但对于来自特定丘脑区域的神经支配差异知之甚少。参与这两种输出通路的丘脑对胆碱能神经元和棘神经元输入的差异将被检查，并确定这些细胞的形态和其他传入。通过标记释放机制的组成部分，然后将它们与多巴胺受体的位置相关联，来评估黑质纹状体DA传入的非突触释放位点的可能性。

DESCRIPTION: (Adapted From The Applicant's Abstract) This application seeks renewal of research support to continue to study the sites and mechanisms of action of psychomotor stimulants. Its general aim is to study the effects of amphetamine on striatal glutamate and dopamine neurotransmission and the sites of termination of glutamate and dopamine axons relative to the different neostriatal output cells. Specifically, it will address three issues related to the effects of systemic amphetamine: the presynaptic mechanisms contributing to neostriatal changes associated with addiction, and the circuitry that brings about the amphetamine-induced increase in neuronal activity of the direct striatal output pathway. The motor effects of these drugs depend on their ability to increase dopamine (DA) transmission. Several motor responses are enhanced by repeated amphetamine administration; a phenomenon termed behavioral sensitization. Changes in the sensitivity of DA somatodendritic and terminal axon autoreceptors may contribute to behavioral sensitization. Experiments are proposed using terminal excitability, an in vivo electro- physiological measure of presynaptic receptor stimulation, and microdialysis to further study the bases for presynaptic changes in nigrostriatal DA axon terminals in sensitized rats. DA terminal fields in nucleus accumbens and prefrontal cortex will also be examined. Alterations in glutamatergic transmission may also be critical in the development of sensitization. Excitability measurements will assess possible presynaptic changes in the glutamatergic afferents to the neostriatum, nucleus accumbens and ventral tegmental area. Other studies will examine the relation between impulse-induced long-lasting changes in presynaptic corticostriatal excitability and postsynaptic expressions of long- term potentiation or depression. Electron microscopic studies are proposed to further elucidate the neostriatal circuitry involving the DA and glutamate afferent systems. It will be determined whether DA inputs onto spiny dendrites 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 and indirect output pathways. The thalamus is a major excitatory input to the striatum, yet little is known regarding differences in innervation from specific thalamic regions. Differences in the thalamic input onto cholinergic and spiny neurons participating in the two output pathways will be examined and the morphology and other afferents of these cells determined. The possibility of nonsynaptic release sites on nigrostriatal DA afferents will be assessed by labeling components of the release mechanism and then correlating them with the locations of dopamine receptors.