Schizophrenia and Cognitive Disorders Discovery Performance Unit, Neurosciences Centre of Excellence for Drug Discovery, GlaxoSmithKline Research & Development Ltd, New Frontiers Science Park, Harlow, Essex, CM19 5AW, UK.
Behav Brain Res. 2012 Mar 1;228(1):211-8. doi: 10.1016/j.bbr.2011.12.009. Epub 2011 Dec 16.
The 5-hydroxytryptamine7 (5-HT7) receptor is a G-protein coupled receptor for serotonin that has been implicated in the pathophysiology of psychiatric and neurological disorders including anxiety, depression and schizophrenia. A number of studies have attempted to evaluate the potential role of the 5-HT7 receptor in schizophrenia by utilising genetic or pharmacological tools but to date these have provided conflicting results. Here we investigate the effect of a selective 5-HT7 receptor antagonist, SB-269970, in in vivo psychosis and cognition models and relate efficacy to brain exposures of the compound. SB-269970 significantly attenuated amphetamine-induced rearing and circling in rats. A similar effect was observed in an N-methyl d-aspartic acid (NMDA) receptor antagonist driven psychosis model, where SB-269970 significantly reversed phencyclidine-induced hyperlocomotion, rearing and circling; although the effect was not as robust as with the 5-HT2a receptor antagonist positive control, MDL100,907. SB-269970 also attenuated a temporal deficit in novel object recognition (NOR), indicative of an improvement in recognition memory. Pharmacokinetic analysis of plasma and brain samples taken after behavioural testing confirmed that efficacy was achieved at doses and pre-treatment times where receptor occupancy was substantial. These findings highlight the anti-psychotic and pro-cognitive potential of 5-HT7 receptor antagonists and warrant further studies to explore their therapeutic potential in schizophrenia.
5-羟色胺 7（5-HT7）受体是一种血清素的 G 蛋白偶联受体，与包括焦虑、抑郁和精神分裂症在内的精神和神经疾病的病理生理学有关。许多研究试图利用遗传或药理学工具来评估 5-HT7 受体在精神分裂症中的潜在作用，但迄今为止，这些研究提供了相互矛盾的结果。在这里，我们研究了选择性 5-HT7 受体拮抗剂 SB-269970 在体内精神病和认知模型中的作用，并将疗效与化合物的脑暴露相关联。SB-269970 显著减弱了安非他命诱导的大鼠出现的举肢和转圈行为。在 N-甲基-D-天冬氨酸（NMDA）受体拮抗剂驱动的精神病模型中也观察到类似的效果，其中 SB-269970 显著逆转了苯环己哌啶诱导的过度活动、举肢和转圈行为；尽管与 5-HT2a 受体拮抗剂阳性对照 MDL100907 相比，效果并不那么显著。SB-269970 还减轻了在新物体识别（NOR）中的时间缺陷，表明对识别记忆的改善。在行为测试后采集的血浆和脑组织样本的药代动力学分析证实，在受体占有率较高的剂量和预处理时间下，能够实现疗效。这些发现突出了 5-HT7 受体拮抗剂的抗精神病和促认知潜力，值得进一步研究以探索它们在精神分裂症中的治疗潜力。
