Winkler J D, Weiss B
Department of Pharmacology, Medical College of Pennsylvania at Eastern Pennsylvania Psychiatric Institute, Philadelphia.
J Pharmacol Exp Ther. 1989 May;249(2):507-16.
The effects of continuous exposure to selective dopaminergic agonists were examined in mice with unilateral 6-hydroxydopamine-induced lesions of the corpus striatum. Continuously infusing the D1 agonists, SKF 38393, SKF 75670 and Cy 208-243 with the use of implanted Alzet minipumps initially produced rotational behavior, but this effect decreased during the first 2 days and then stopped completely during days 3 to 7 of drug infusion. Infusion of the D2 agonists quinpirole and N-0437 also produced rotational behavior but, in contrast to the results seen with the D1 agonists, the rotational response remained present throughout the 7 days of drug exposure. The desensitization produced by continuous exposure to SKF 38393 was selective for the D1 system, as animals exposed continuously to SKF 38393 failed to rotate to an acute challenge dose of SKF 38393 but had a normal rotational response to quinpirole. SKF 75670 and CY 208-243 were less selective than SKF 38393; continuous exposure to SKF 75670 and CY 208-243 decreased the response to an acute injection of D1-agonists by 98 and 95%, respectively, and to that of D2-agonists by 64 and 38%, respectively. Infusing the peripherally acting D1 agonist, fenoldopam, or the inactive isomer (-)-SKF 38393 failed to produce desensitization, suggesting that SKF 38393-induced desensitization is produced by an action at D1 receptors within the central nervous system. These results demonstrate that the D1 system can be desensitized independently from the D2 system and that there are different mechanisms for the long term regulation of D1 and D2 dopaminergic systems.
在单侧6-羟基多巴胺诱导纹状体损伤的小鼠中，研究了持续暴露于选择性多巴胺能激动剂的影响。使用植入式Alzet微型泵持续输注D1激动剂SKF 38393、SKF 75670和Cy 208-243，最初会产生旋转行为，但这种效应在最初2天内会减弱，然后在药物输注的第3至7天完全停止。输注D2激动剂喹吡罗和N-0437也会产生旋转行为，但与D1激动剂的结果相反，在药物暴露的7天内旋转反应一直存在。持续暴露于SKF 38393所产生的脱敏作用对D1系统具有选择性，因为持续暴露于SKF 38393的动物对SKF 38393的急性挑战剂量不再旋转，但对喹吡罗仍有正常的旋转反应。SKF 75670和CY 208-243的选择性低于SKF 38393；持续暴露于SKF 75670和CY 208-243分别使对D1激动剂急性注射的反应降低了98%和95%，对D2激动剂急性注射的反应分别降低了64%和38%。输注外周作用的D1激动剂非诺多泮或无活性异构体(-)-SKF 38393不会产生脱敏作用，这表明SKF 38393诱导的脱敏作用是由中枢神经系统内D1受体的作用产生的。这些结果表明，D1系统可以独立于D2系统发生脱敏，并且D1和D2多巴胺能系统的长期调节存在不同机制。
