Isacson R, Kull B, Wahlestedt C, Salmi P
Center for Genomics and Bioinformatics, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
Neuroscience. 2004;124(1):33-42. doi: 10.1016/j.neuroscience.2003.11.016.
The behavioral and biochemical effects of the full dopamine D(1/5) receptor agonists, dihydrexidine and (1R,3S)-1-aminomethyl-5,6-dihydroxy-3-phenylisochroman HCl (A 68930), were examined in rats. Both A 68930 (0-4.6 mg kg(-1), s.c.) and dihydrexidine (0-8.0 mg kg(-1), s.c.) caused a dose-dependent suppression of locomotor activity, as assessed in an open-field. This locomotor suppression was dose-dependently antagonized by the selective dopamine D(1/5) receptor antagonist R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine HCl (SCH 23390; 0-5.0 microg kg(-1), s.c.), but not by the selective dopamine D(2/3) receptor antagonist raclopride (0-25.0 microg kg(-1), s.c.). Furthermore, A 68930 and dihydrexidine did not cause any locomotor activity in habituated rats that displayed a very low base-line activity. Neither did A 68930 nor dihydrexidine produce any excessive stereotypies that could possibly interfere with and mask ambulatory activity. In fact, both A 68930 and dihydrexidine potently blocked hyperactivity produced by d-amphetamine (0-4.0 mg kg(-1), s.c.). Such findings traditionally would be interpreted as a sign of potential antipsychotic properties of A 68930 and dihydrexidine. Examination of neuronal activation, as indexed by the immediate early gene c-fos, showed that A 68930 and dihydrexidine caused a highly significant expression of c-fos in the medial prefrontal cortex. This c-fos expression was sensitive to treatment with SCH 23390, but not with raclopride. The effects of A 68930 and dihydrexidine on c-fos expression in caudate putamen or nucleus accumbens were less marked, or undetectable. The results indicate that stimulation of dopamine D(1/5) receptors, possibly in the medial prefrontal cortex, is associated with inhibitory actions on locomotor activity and d-amphetamine-induced hyperactivity. Assuming an important role of prefrontal dopamine D(1/5) receptors in schizophrenia, such inhibitory actions of dopamine D(1/5) receptor stimulation on psychomotor activation may have interesting clinical implications in the treatment of schizophrenia.
在大鼠中研究了全多巴胺D(1/5)受体激动剂二氢麦角隐亭和(1R,3S)-1-氨基甲基-5,6-二羟基-3-苯基异苯并二氢吡喃盐酸盐（A 68930）的行为和生化效应。在旷场实验中评估发现，A 68930（0 - 4.6 mg kg(-1)，皮下注射）和二氢麦角隐亭（0 - 8.0 mg kg(-1)，皮下注射）均引起剂量依赖性的运动活动抑制。这种运动抑制可被选择性多巴胺D(1/5)受体拮抗剂R(+)-7-氯-8-羟基-3-甲基-1-苯基-2,3,4,5-四氢-1H-3-苯并氮杂卓盐酸盐（SCH 23390；0 - 5.0 μg kg(-1)，皮下注射）剂量依赖性地拮抗，但不能被选择性多巴胺D(2/3)受体拮抗剂雷氯必利（0 - 25.0 μg kg(-1)，皮下注射）拮抗。此外，A 68930和二氢麦角隐亭对基线活动非常低的习惯化大鼠未引起任何运动活动。A 68930和二氢麦角隐亭均未产生任何可能干扰和掩盖自主活动的过度刻板行为。事实上，A 68930和二氢麦角隐亭均有效阻断了由d-苯丙胺（0 - 4.0 mg kg(-1)，皮下注射）引起的多动。传统上，这些发现会被解释为A 68930和二氢麦角隐亭具有潜在抗精神病特性的迹象表现。以即刻早期基因c-fos为指标检测神经元激活情况，结果显示A 68930和二氢麦角隐亭在内侧前额叶皮层引起了c-fos的高度显著表达。这种c-fos表达对SCH 23390治疗敏感，但对雷氯必利不敏感。A 68930和二氢麦角隐亭对尾状壳核或伏隔核中c-fos表达的影响较不明显或无法检测到。结果表明，可能在内侧前额叶皮层中多巴胺D(1/5)受体的刺激与对运动活动和d-苯丙胺诱导的多动的抑制作用相关。假设前额叶多巴胺D(1/5)受体在精神分裂症中起重要作用，那么多巴胺D(1/5)受体刺激对精神运动激活的这种抑制作用在精神分裂症治疗中可能具有有趣的临床意义。
