Neurochemical and pharmaco-behavioural studies on the biological basis of oral dyskinesia

1.口腔运动障碍是一种神经系统综合征，与衰老或使用神经抑制剂和帕金森病药物有关。它的特点是重复刻板的口腔运动。详细的病理生理基础的障碍仍然不清楚，但行为学研究表明，增加多巴胺（DA）的功能在纹状体和脑桥核的生产重复下颌运动的大鼠的意义。为了探讨DA功能增强的生物学基础，我们着重研究了（1）纹状体内注射右旋苯丙胺对纹状体DA外排的作用，（2）纹状体内注射δ受体激动剂TAN-67对纹状体DA外排的作用，（3）纹状体内注射内吗啡肽（EM）-2和EM-1，内源性μ受体激动剂对纹状体DA外排的影响;（4）局部输注α-甲基-β-酪氨酸（AMPT），一种酪氨酸羟化酶抑制剂对纹状体和纹状体DA外排的影响。在体脑微透析法检测DA水平。2.本研究发现：（1）囊泡和胞浆DA池均参与了纹状体内注射右旋苯丙胺引起的DA外排。（2）（-）-TAN-67可产生大量自由基，引发谷氨酸释放，最终激活NMDA受体，提高脑内DA水平。（3）脑内注射EM-2和EM-1可通过不同的机制增加多巴胺的外排。因此，EM-2的作用不是通过阿片受体介导的，而EM-1的作用是通过μ 1-阿片受体介导的。（4）AMPT的局部输注是分析特定脑区域内AMPT敏感DA池的作用的有价值的工具，但它不能用于比较不同脑结构的作用，因为固定剂量的AMPT对丘脑和背侧纹状体的影响不同。

1.Oral dyskinesia is a neurological syndrome associated with aging or use of neuroleptics and drugs for Parkinson's disease. It is characterized by repetitive stereotyped oral movement. The detailed pathophysiological basis of the disorder remains unclear, but behavioural studies suggest the significance of increase in dopamine (DA) function in the striatum and nucleus accumbens for the production of repetitive jaw movements of rats. In order to investigate the biological basis of the enhancement of DA function, we focused on the mechanisms of action of (1)the intrastriatal injection of dexamphetamine on the striatal DA efflux, (2)the intraaccumbal infusion of the putative delta receptor agonist TAN-67 on the accumbal DA efflux, (3)the intraaccumbal infusion of endomorphin (EM)-2 and EM-1, the endogenous mu receptor agonists on the accumbal DA efflux and (4)the local infusion of alpha-methyl-p-tyrosine (AMPT), a tyrosine hydroxylase inhibitor on the striatal and accumbal DA efflux. The DA levels were monitored by in vivo brain microdialysis.2.The present study reveals that (1)both vesicular and cytosolic DA pools contribute to the intrastriatal injection of dexamphetamine-induced striatal DA efflux. (2)(-)-TAN-67 can generate a burst of free radicals that trigger glutamate release which ultimately activates NMDA receptors that enhance the accumbal DA levels. (3)The intraaccumbal infusion of EM-2 and EM-1 increase accumbal DA efflux by mechanisms that differ. Thus, the effects of EM-2 are not mediated via opioid receptors in contrast to the effects of EM-1 that are mediated via mu1-opioid receptors. (4)The local infusion of AMPT is a valuable tool for analyzing the role of AMPT-sensitive DA pools within a particular brain area, but it cannot be used to compare effects across different brain structures, since a fixed dose of AMPT differentially affects the nucleus accumbens and dorsal striatum.