MECHANISM OF ACTION OF DRUGS OF ABUSE--AMPHETAMINE

滥用药物--安非他明的作用机制

• 批准号: 6175135
• 负责人: PHILIP M GROVES
• 金额: $ 16.76万
• 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: 1993-04-01 至 2004-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6175135
• 关键词: amphetamines; behavioral habituation /sensitization; brain mapping; brain metabolism; dopamine; dopamine receptor; drug metabolism; electron microscopy; electrophysiology; glutamate receptor; immunocytochemistry; laboratory rat; neural transmission; neurochemistry; pharmacokinetics; synapses

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.

描述：（改编自申请人的摘要）本申请寻求更新的研究支持，以继续研究精神运动兴奋剂的作用位点和机制。其总体目标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：导致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直接纹状体输出途径神经元活动增加的电路。这些药物的运动作用取决于它们增加多巴胺 (DA) 传输的能力。重复使用安非他明可增强多种运动反应；一种称为行为敏化的现象。 DA 体细胞树突和末端轴突自身受体敏感性的变化可能有助于行为敏化。建议使用末端兴奋性（突触前受体刺激的体内电生理测量）和微透析进行实验，以进一步研究致敏大鼠黑质纹状体 DA 轴突末端突触前变化的基础。伏隔核和前额皮质的 DA 末端区域也将被检查。谷氨酸能传递的改变对于致敏的发展也可能是至关重要的。兴奋性测量将评估新纹状体、伏核和腹侧被盖区的谷氨酸传入神经可能发生的突触前变化。其他研究将检查冲动引起的突触前皮质纹状体兴奋性的长期变化与突触后长期增强或抑制的表达之间的关系。建议进行电子显微镜研究以进一步阐明涉及 DA 和谷氨酸传入系统的新纹状体回路。将确定多刺树突上的 DA 输入是否与来自特定皮质和丘脑区域的输入相关，以及这些收敛模式对于被识别为属于直接和间接输出途径的多刺神经元是否不同。丘脑是纹状体的主要兴奋输入，但对于特定丘脑区域的神经支配差异知之甚少。将检查参与两个输出途径的胆碱能和棘神经元的丘脑输入的差异，并确定这些细胞的形态和其他传入神经。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，可以评估黑质纹状体 DA 传入神经上非突触释放位点的可能性。