MECHANISM OF ACTION OF DRUGS OF ABUSE--AMPHETAMINE

描述：(改编自申请人的摘要)本申请寻求续期研究支持，以继续研究精神运动兴奋剂的作用部位和作用机制。其主要目的是研究苯丙胺对纹状体谷氨酸和多巴胺神经传递的影响，以及谷氨酸和多巴胺轴突相对于不同新纹状体输出细胞的终止部位。具体地说，它将解决与全身性苯丙胺的影响有关的三个问题：与成瘾相关的新纹状体变化的突触前机制，以及导致苯丙胺诱导的纹状体直接输出通路神经元活动增加的回路。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。反复服用安非他明会增强几种运动反应；这种现象被称为行为敏感化。多巴体树突和终末轴突自身受体敏感性的改变可能与行为敏感化有关。为进一步研究致敏大鼠黑质纹状体DA轴突终末突触前改变的基础，提出了利用终末兴奋性和微透析进一步研究致敏大鼠黑质纹状体DA轴突终末突触前变化的实验。伏隔核和前额叶皮质的DA终末野也将被检查。谷氨酸能传递的改变在敏感化的发展中也可能是关键的。兴奋性测量将评估新纹状体、伏隔核和腹侧被盖区谷氨酸能传入的可能突触前变化。其他研究将检验脉冲诱导的突触前皮质纹状体兴奋性的长期变化与突触后长时程增强或抑郁表达之间的关系。建议通过电子显微镜研究进一步阐明涉及DA和谷氨酸传入系统的新纹状体回路。将确定DA在棘树突上的输入是否与来自特定皮质和丘脑区域的输入有关，以及属于直接和间接输出通路的棘神经元的这些汇聚模式是否不同。丘脑是纹状体的主要兴奋性输入，但对特定丘脑区域的神经支配差异知之甚少。将检查丘脑对参与两条输出通路的胆碱能神经元和棘神经元的输入的差异，并确定这些细胞的形态和其他传入细胞。黑质纹状体DA传入的非突触释放部位的可能性将通过标记释放机制的组件，然后将它们与多巴胺受体的位置相关联来评估。

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.