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

通过检查基底神经节的功能，特别是核内受体-受体相互作用，研究了药物诱导的口腔运动障碍发展的潜在机制。在大鼠下颌运动模型的研究中，为纹状体腹外侧区血管紧张素AT_1受体在多巴胺D_1/D_2受体介导的刻板下颌运动中的调节作用提供了证据。此外，还发现位于基底节输出部位的GABA_A受体在D_1/D_2受体介导的重复性颌运动的产生中起重要作用。此外，自发性高血压大鼠纹状体腹外侧区突触后D_1/D_2受体和乙酰胆碱受体的功能也降低。在用多巴胺受体亚型敲除的突变小鼠进行的下颌运动研究中，发现D_2受体对个体的口面运动地形图具有不同的调节方式，有时与其D_2受体相反<1A>。在大鼠翻转模型的研究中发现，延髓背核壳内阿片受体、AMPA受体、NMDA受体和GABA_A受体在诱导壳特异性D_1/D_2受体介导的翻转行为中起重要作用。此外，脚桥被盖核在D_1/D_2受体介导的壳特异性转向行为的显示中起着中继站的作用。在使用体内脑微透析的研究中，提供了推定的选择性阿片受体激动剂TAN-67、内吗啡肽-1和内吗啡肽-2对纹状体多巴胺释放机制的特征性概况的证据。

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.