Carlsson M L, Martin P, Nilsson M, Sorensen S M, Carlsson A, Waters S, Waters N
Department of Pharmacology, University of Göteborg, Sweden.
J Neural Transm (Vienna). 1999;106(2):123-9. doi: 10.1007/s007020050144.
The purpose of the present study was to compare the effectiveness of the selective 5-HT2A antagonist M100907 in different psychosis models. The classical neuroleptic haloperidol was used as reference compound. Two hyperdopaminergia and two hypoglutamatergia mouse models were used. Hyperdopaminergia was produced by the DA releaser d-amphetamine or the DA uptake inhibitor GBR 12909. Hypoglutamatergia was produced by the un-competitive NMDA receptor antagonist MK-801 or the competitive NMDA receptor antagonist D-CPPene. M100907 was found to counteract the locomotor stimulant effects of the NMDA receptor antagonists MK-801 and D-CPPene, but spontaneous locomotion, d-amphetamine- and GBR-12909-induced hyperactivity were not significantly affected. Haloperidol, on the other hand, antagonized both NMDA antagonist- and DA agonist-induced hyperactivity, as well as spontaneous locomotion in the highest dose used. Based on the present and previous results we draw the conclusion that 5-HT2A receptor antagonists are particularly effective against behavioural anomalies resulting from hypoglutamatergia of various origins. The clinical implications of our results and conclusions would be that a 5-HT2A receptor antagonist, due to i a the low side effect liability, could be the preferable treatment strategy in various disorders associated with hypoglutamatergia; such conditions might include schizophrenia, childhood autism and dementia disorders.
本研究的目的是比较选择性5-HT2A拮抗剂M100907在不同精神病模型中的效果。经典抗精神病药物氟哌啶醇用作参考化合物。使用了两种多巴胺能亢进和两种谷氨酸能低下小鼠模型。多巴胺能亢进由多巴胺释放剂d-苯丙胺或多巴胺摄取抑制剂GBR 12909诱导产生。谷氨酸能低下由非竞争性NMDA受体拮抗剂MK-801或竞争性NMDA受体拮抗剂D-CPPene诱导产生。发现M100907可抵消NMDA受体拮抗剂MK-801和D-CPPene的运动兴奋作用，但对自发运动、d-苯丙胺和GBR-12909诱导的多动没有显著影响。另一方面，氟哌啶醇在所用的最高剂量下可拮抗NMDA拮抗剂和多巴胺激动剂诱导的多动以及自发运动。基于目前和先前的结果，我们得出结论，5-HT2A受体拮抗剂对各种原因引起的谷氨酸能低下导致的行为异常特别有效。我们的结果和结论的临床意义在于，由于5-HT2A受体拮抗剂副作用较小，可能是治疗与谷氨酸能低下相关的各种疾病（如精神分裂症、儿童自闭症和痴呆症）的首选治疗策略。
