Gravius Andreas, Laszy Judit, Pietraszek Malgorzata, Sághy Katalin, Nagel Jens, Chambon Caroline, Wegener Nico, Valastro Barbara, Danysz Wojciech, Gyertyán István
Departments of In vivo Pharmacology bIn vitro Pharmacology, Merz Pharmaceuticals GmbH, Frankfurt, Germany.
Behav Pharmacol. 2011 Apr;22(2):122-35. doi: 10.1097/FBP.0b013e328343d804.
5-Hydroxytryptamine 6 (5-HT6) receptors are involved in learning and memory processes and are discussed as promising targets for the treatment of cognitive impairment in central nervous system disorders. A number of 5-HT6 antagonists are currently in the clinical development for schizophrenia and Alzheimer's disease (AD). There is some discrepancy regarding cognitive efficacy in subjects, and only limited data are available on the role of the 5-HT6 receptor in animal models of psychosis. The aim of this study was to investigate the efficacy of the selective 5-HT6 antagonists, Ro-4368554 (1-10 mg/kg, intraperitoneally) and SB-258585 (3-30 mg/kg, intraperitoneally), in animal models for schizophrenia and AD. Both compounds showed cognition-enhancing effects in object recognition, whereas only SB-258585 was able to prevent the scopolamine-induced deficit in the Morris water-maze test. Neither Ro-4368554 nor SB-258585 prevented scopolamine-induced impairment in contextual fear conditioning. Similarly, both compounds were ineffective on MK-801-induced deficits in contextual fear conditioning and spatial working memory. Ro-4368554, but not SB-258585 reversed the apomorphine-induced deficit in prepulse inhibition. Amphetamine-induced hyperlocomotion was not affected by either compound. Taken together, the overall efficacy of Ro-4368554 and SB-258585 in animal models for AD and schizophrenia is rather limited. These data show moderate efficacy in some models for AD but do not support the therapeutic potential of 5-HT6 antagonists for schizophrenia.
5-羟色胺6（5-HT6）受体参与学习和记忆过程，被视为治疗中枢神经系统疾病认知障碍的潜在靶点。目前，多种5-HT6拮抗剂正处于治疗精神分裂症和阿尔茨海默病（AD）的临床开发阶段。然而，这些拮抗剂在人体中的认知疗效存在差异，且关于5-HT6受体在精神病动物模型中的作用仅有有限的数据。本研究旨在探讨选择性5-HT6拮抗剂Ro-4368554（1-10毫克/千克，腹腔注射）和SB-258585（3-30毫克/千克，腹腔注射）在精神分裂症和AD动物模型中的疗效。两种化合物在物体识别实验中均显示出认知增强作用，但只有SB-258585能够预防东莨菪碱诱导的Morris水迷宫实验中的缺陷。Ro-4368554和SB-258585均不能预防东莨菪碱诱导的情境恐惧条件反射损伤。同样，两种化合物对MK-801诱导的情境恐惧条件反射和空间工作记忆缺陷均无效。Ro-4368554能逆转阿扑吗啡诱导的前脉冲抑制缺陷，而SB-258585则不能。两种化合物均未影响苯丙胺诱导的运动亢进。综上所述，Ro-4368554和SB-258585在AD和精神分裂症动物模型中的总体疗效相当有限。这些数据表明，它们在某些AD模型中具有中等疗效，但不支持5-HT6拮抗剂对精神分裂症的治疗潜力。
