Hu X T, Brooderson R J, White F J
Department of Psychiatry, Wayne State University School of Medicine, Lafayette Clinic, Detroit, MI 48207.
Neuroscience. 1992 Sep;50(1):137-47. doi: 10.1016/0306-4522(92)90388-i.
Recent evidence suggests that repeated stimulation of D1 dopamine receptors within the rat striatum leads to an enhancement of both D1 and D2 dopamine receptor-mediated responses. The present study used both behavioral observations and extracellular single unit recording techniques to investigate this phenomenon following repeated administration of selective D1 dopamine receptor agonists. Groups of rats received twice daily administration of either saline or the partial D1 dopamine receptor agonist SKF 38393 (8 mg/kg, s.c.) for three weeks. Rats were tolerant to the ability of SKF 38393 to enhance grooming behavior when tested immediately following the last of the 42 treatment injections. However, the ability of this last SKF 38393 injection to potentiate oral stereotyped behavior following administration of the D2 DA agonist quinpirole was still evident. Following a one-day withdrawal, grooming responses to SKF 38393 had returned to normal. At this time, administration of quinpirole, without concomitant SKF 38393, failed to significantly promote oral stereotypies, as is typical of normal rats. Following a one-week withdrawal period, SKF 38393-induced grooming behavior was significantly enhanced and quinpirole, administered without SKF 38393, produced pronounced oral stereotyped behavior in 10 of 12 rats tested. Following a one-month withdrawal, these sensitized responses were no longer evident. Single-cell recordings from rat lateral striatal neurons revealed similar time-dependent alterations in the effects of iontophoretically administered SKF 38393 and quinpirole. Current-response curves revealed that, without a withdrawal period, striatal neurons were subsensitive to the inhibitory effects of SKF 38393 but not quinpirole. The decreased inhibitory responses of striatal neurons to SKF 38393 returned to normal levels after a one-day withdrawal. Following a one-week withdrawal, the effects of both agonists were significantly greater than that in saline-treated controls. Normosensitivity was evident following a one-month withdrawal. Repeated administration of the full D1 DA agonist SKF 81297 (0.5 mg/kg, s.c., twice daily) also resulted in sensitized responses of striatal neurons following a one-week withdrawal, demonstrating that the sensitization to SKF 38393 was not due to its partial agonist character. The present findings provide both behavioral and electrophysiological evidence that repeated stimulation of D1 dopamine receptors results in a brief subsensitivity, followed by transient sensitization of the D1 receptors. The enhanced effects of D2 dopamine agonists might be due to an enhanced synergism (enabling) produced by endogenous dopamine stimulating supersensitive D1 receptors.(ABSTRACT TRUNCATED AT 400 WORDS)
近期证据表明，对大鼠纹状体内的D1多巴胺受体进行反复刺激会导致D1和D2多巴胺受体介导的反应均增强。本研究采用行为观察和细胞外单单位记录技术，来探究在反复给予选择性D1多巴胺受体激动剂后出现的这一现象。将大鼠分组，每天两次给予生理盐水或部分D1多巴胺受体激动剂SKF 38393（8毫克/千克，皮下注射），持续三周。在42次治疗注射中的最后一次注射后立即进行测试时，大鼠对SKF 38393增强梳理行为的能力产生了耐受性。然而，最后一次SKF 38393注射在给予D2多巴胺激动剂喹吡罗后增强口腔刻板行为的能力仍然明显。在停药一天后，对SKF 38393的梳理反应恢复正常。此时，单独给予喹吡罗（不伴有SKF 38393）未能显著促进口腔刻板行为，这是正常大鼠的典型表现。在停药一周后，SKF 38393诱导的梳理行为显著增强，并且在12只接受测试的大鼠中有10只在不给予SKF 38393的情况下给予喹吡罗时出现了明显的口腔刻板行为。在停药一个月后，这些敏感化反应不再明显。对大鼠外侧纹状体神经元的单细胞记录显示，离子电渗法给予SKF 38393和喹吡罗的效果存在类似的时间依赖性变化。电流-反应曲线显示，在没有停药期的情况下，纹状体神经元对SKF 38393的抑制作用不敏感，但对喹吡罗敏感。纹状体神经元对SKF 38393的抑制反应降低在停药一天后恢复到正常水平。在停药一周后，两种激动剂的作用均显著大于生理盐水处理的对照组。在停药一个月后恢复正常敏感性。反复给予完全D1多巴胺激动剂SKF 81297（0.5毫克/千克，皮下注射，每天两次）在停药一周后也导致纹状体神经元出现敏感化反应，表明对SKF 38393的敏感化并非因其部分激动剂特性所致。本研究结果提供了行为学和电生理学证据，即对D1多巴胺受体的反复刺激会导致短暂的不敏感，随后是D1受体的短暂敏感化。D2多巴胺激动剂作用增强可能是由于内源性多巴胺刺激超敏感的D1受体产生的协同作用增强所致。（摘要截选至400字）
