Goldstein M, Kuga S, Kusano N, Meller E, Dancis J, Schwarcz R
Brain Res. 1986 Mar 5;367(1-2):114-20. doi: 10.1016/0006-8993(86)91584-2.
We have investigated the effects of various dopamine (DA) agonists on induction of abnormal involuntary movements (AIM) in a group of monkeys which had denervated nigro-striatal DA neurons for 10-14 years rendered by a unilateral surgical ventromedial tegmental (VMT) lesion of the brainstem. The surgical lesions were placed when the monkeys were 2-4 years old. The administration of mixed DA agonists, such as L-DOPA, apomorphine (Apo) and abeorphine 201-678, elicit a self-mutilative biting behavior (SMB) of the forelimb digits contralateral to the lesion, and spasticity of the contralateral hindlimb. These dysfunctions resemble, in some aspects, the neurological disturbances associated with Lesch-Nyhan syndrome. The SMB behavior was elicited by mixed DA agonists which predominantly stimulate D1, but not D2 DA receptors, and was prevented or abolished by the D1 DA antagonist SCH 23390 or by the D1 and D2 DA antagonist fluphenazine (Flu), but not by the D2 antagonist (+/-)sulpiride. These results suggest that DA agonist-induced SMB behavior is mediated by D1 and/or by both D1 and D2 DA receptor pathways. To study the relationships between HPRT, the defective enzyme in Lesch-Nyhan syndrome, and the DA neuronal systems, we have measured the effects of nigro-striatal DA degeneration and intrastriatal neuronal degeneration on HPRT activity. The unilateral 6-OHDA-induced nigro-striatal DA degeneration does not significantly alter the HPRT activity on the lesioned side of the striatum, while the quinolinic acid-induced intrastriatal neuronal degeneration significantly reduces the enzyme activity. These results suggest that HPRT is localized on intrastriatal neurons which are also known to contain DA receptors. It is postulated that HPRT deficiency in Lesch-Nyhan syndrome results in abnormal guanine nucleotide metabolism which may affect the regulation of DA receptors.
我们研究了各种多巴胺（DA）激动剂对一组猴子异常不自主运动（AIM）诱导的影响。这些猴子因脑干单侧手术腹内侧被盖区（VMT）损伤，导致黑质纹状体DA神经元失神经支配10 - 14年。手术损伤在猴子2 - 4岁时进行。给予混合DA激动剂，如左旋多巴、阿扑吗啡（Apo）和阿贝吗啡201 - 678，会引发损伤对侧前肢手指的自残性咬行为（SMB）以及对侧后肢的痉挛。这些功能障碍在某些方面类似于与莱施 - 奈恩综合征相关的神经紊乱。SMB行为由主要刺激D1而非D2 DA受体的混合DA激动剂引发，并被D1 DA拮抗剂SCH 23390或D1和D2 DA拮抗剂氟奋乃静（Flu）预防或消除，但不被D2拮抗剂（±）舒必利消除。这些结果表明，DA激动剂诱导的SMB行为是由D1和/或D1和D2 DA受体途径介导的。为了研究莱施 - 奈恩综合征中缺陷酶次黄嘌呤 - 鸟嘌呤磷酸核糖基转移酶（HPRT）与DA神经元系统之间的关系，我们测量了黑质纹状体DA变性和纹状体内神经元变性对HPRT活性的影响。单侧6 - 羟基多巴胺（6 - OHDA）诱导的黑质纹状体DA变性并未显著改变纹状体损伤侧的HPRT活性，而喹啉酸诱导的纹状体内神经元变性则显著降低了该酶的活性。这些结果表明，HPRT定位于纹状体内神经元，而这些神经元也已知含有DA受体。据推测，莱施 - 奈恩综合征中HPRT缺乏导致鸟嘌呤核苷酸代谢异常，这可能会影响DA受体的调节。
