Studies on the mechanisms involved in the development of drug-induced oral dyskinesia

通过检测基底节的功能，特别是与核内受体-受体的相互作用，研究了药物诱导的口腔运动障碍发生的潜在机制。在大鼠颌骨移动模型的研究中，纹状体腹外侧纹状体血管紧张素AT_1受体在多巴胺D_1/D_2受体介导的颌骨刻板运动中的调节作用提供了证据。在D_1/D_2受体介导的重复性颌骨运动中，上丘、腰后野和腹侧苍白球等基底节输出部位的GABA_A受体起重要作用。此外，自发性高血压大鼠腹外侧纹状体突触后D_1/D_2受体和乙酰胆碱受体功能降低。在使用同种多巴胺受体亚型基因敲除的突变小鼠进行的下颌运动研究中，发现D_2受体以一种截然不同的方式对个体口腔面部运动地形起着不同的调节作用，有时甚至与它们的D_1a和gt；受体相反。相反，D_3、D_4和D_5受体对这种运动的调节作用较小。在大鼠翻身模型的研究中，发现伏隔核壳层中的阿片、AMPA、NMDA和GABA_A受体在诱导壳特异性D_1/D_2受体介导的翻身行为中起重要作用。此外，桥小脑脚被盖核在显示壳特异性D_1/D_2受体介导的翻转行为中起中继站的作用。在利用活体脑微透析的研究中，为可能的选择性阿片受体激动剂Tan-67、内吗啡-1和内吗啡-2对纹状体多巴胺释放机制的特征提供了证据。

The mechanisms underlying the development of drug-induced oral dyskinesia were studied by examining functions of the basal ganglia, particularly with respect to receptor-receptor interactions within the nucleus. In the studies using rat jaw moving model, evidence was provided for the regulatory role of striatal angiotensin AT_1 receptors in the ventrolateral striatum in dopamine D_1/D_2 receptor-mediated stereotyped jaw movements. It was also provided that GABA_A receptors in the output stations from the basal ganglia, such as the superior colliculus, retrorubral field and ventral pallidum, play an important role in the production of D_1/D_2 receptor-mediated repetitive jaw movements. In addition, reduction in the functions of postsynaptic D_1/D_2 receptors and acetylcholine receptors in the ventrolateral striatum was found in spontaneously hypertensive rats. In jaw movement studies using mutant mice with congenic dopamine receptor subtypes knockout, it was found that D_2 receptors exert differential regulation of individual orofacial movement topographies in a manner that is distinct form, and sometimes opposite to, that of their D_<1A> counterparts. Conversely, D_3,D_4 and D_5 receptors exert only miner regulation of such movements.In the studies using rat turning model, it was found that opioid, AMPA, NMDA and GABA_A receptors in the nucleus accumbens shell play an important role in the induction of shell-specific D_1/D_2 receptor-mediated turning behaviour. Moreover, the pedunculopontine tegmental nucleus was shown to play a role as a relay station in the display of the shell-specific D_1/D_2 receptor-mediated turning behaviour. In the studies using in vivo brain microdialysis, evidence for characteristic profiles of putative selective opioid receptor agonists, TAN-67,endomorphin-1 and endomorphn-2, on striatal dopamine release mechanisms was provided.