Hjorth S, Carlsson A
Department of Pharmacology, University of Göteborg, Sweden.
J Neural Transm. 1988;72(2):83-97. doi: 10.1007/BF01250232.
A series of in vivo experiments were undertaken, relating functional (motor activity, body temperature), dopamine (DA) receptor binding and neurochemical (catecholamine synthesis and utilization, DA release) aspects of the pharmacology of SCH23390 in the rat. The compound inhibited the locomotor hyperactivity, but not the hypothermia, induced by the potent DA stimulant DP-5,6-ADTN. Interstingly, SCH23390 simultaneously failed to displace DP-5,6-ADTN from its binding sites in the rat striatum--used as a direct in vivo biochemical index of DA (D-2) receptor interaction. The spontaneous locomotion in non-pretreated rats was likewise inhibited by SCH23390. The locomotor-suppressive action, but not the DP-5,6-ADTN-displacing capacity of the D-2 blocker haloperidol was significantly enhanced by SCH23390, suggesting that motility can be suppressed by either enhanced D-1 or D-2 (postsynaptic) receptor blockade, but also that the D-1 and D-2 sites involved may be physically distinct. SCH23390 only slightly altered in vivo neurochemical of DA synthesis, release and nerve-impulse flow, indicating that, while similar in suppressing dopaminergic behaviour, the D-1 antagonist is less effective than traditional neuroleptics as an activator of DA neuronal feedback mechanisms. The weak increases of DA synthesis and release nonetheless obtained were equal in magnitude (30-40%) in the limbic vs. striatal brain areas; also in this respect, SCH23390 thus differs from classical neuroleptics, which generally display more marked effects in the striatum than in limbic tissue. No major changes in the in vivo indices of NA synthesis and utilization (or in 5-HT synthesis) were found after SCH23390 administration, by and large supporting the DA receptor specificity of the compound. In summary, the studies demonstrated that SCH23390 can offset and accentuate, respectively, behavioural consequences of D-2 receptor stimulation and blockade. Importantly, at the same time no direct interaction at the level of D-2 DA receptor sites in the striatum was detected. Only slight, D-2 antagonist-like, changes in neurochemical indices of dopaminergic activity were observed after D-1 receptor blockade by means of SCH23390. With regard to DA agonist hypothermia, SCH23390 was without effect per se, but (at a high dose) attenuated the action of the D-2 antagonist haloperidol. The observations may indicate that the complex interactions between central D-1 and D-2 receptor-controlled mechanisms that influence behaviour, neurochemistry, and possibly autonomic nervous expression, are not identical.
进行了一系列体内实验，涉及SCH23390在大鼠体内药理学的功能（运动活性、体温）、多巴胺（DA）受体结合以及神经化学（儿茶酚胺合成与利用、DA释放）等方面。该化合物抑制了强效DA兴奋剂DP - 5,6 - ADTN诱导的运动性多动，但未抑制体温过低。有趣的是，SCH23390同时未能将DP - 5,6 - ADTN从大鼠纹状体中的结合位点置换出来，而大鼠纹状体被用作DA（D - 2）受体相互作用的直接体内生化指标。未预处理大鼠的自发运动同样受到SCH23390的抑制。D - 2阻滞剂氟哌啶醇的运动抑制作用（而非DP - 5,6 - ADTN置换能力）被SCH23390显著增强，这表明运动性可以通过增强D - 1或D - 2（突触后）受体阻断来抑制，而且所涉及的D - 1和D - 2位点可能在物理上是不同的。SCH23390仅轻微改变了DA合成、释放和神经冲动流动的体内神经化学过程，这表明，虽然在抑制多巴胺能行为方面相似，但D - 1拮抗剂作为DA神经元反馈机制的激活剂，其效果不如传统抗精神病药物。尽管如此，所获得的DA合成和释放的微弱增加在边缘脑区与纹状体脑区的幅度相同（30 - 40%）；在这方面，SCH23390也不同于经典抗精神病药物，经典抗精神病药物通常在纹状体中比在边缘组织中表现出更显著的效果。给予SCH23390后，未发现去甲肾上腺素合成与利用（或5 - HT合成）的体内指标有重大变化，总体上支持了该化合物的DA受体特异性。总之，研究表明SCH23390可以分别抵消和加剧D - 2受体刺激和阻断的行为后果。重要的是，同时未检测到在纹状体中D - 2 DA受体位点水平上的直接相互作用。通过SCH23390阻断D - 1受体后，仅观察到多巴胺能活性的神经化学指标有轻微的、类似D - 2拮抗剂的变化。关于DA激动剂引起的体温过低，SCH23390本身无作用，但（在高剂量时）减弱了D - 2拮抗剂氟哌啶醇的作用。这些观察结果可能表明，影响行为、神经化学以及可能的自主神经表达的中枢D - 1和D - 2受体控制机制之间的复杂相互作用并不相同。
