Johnson & Johnson Pharmaceutical Research and Development, L.L.C., San Diego, California, United States of America.
PLoS One. 2011;6(6):e20210. doi: 10.1371/journal.pone.0020210. Epub 2011 Jun 20.
The role of 5-HT₇ receptor has been demonstrated in various animal models of mood disorders; however its function in cognition remains largely speculative. This study evaluates the effects of SB-269970, a selective 5-HT₇ antagonist, in a translational model of working memory deficit and investigates whether it modulates cortical glutamate and/or dopamine neurotransmission in rats. The effect of SB-269970 was evaluated in the delayed non-matching to position task alone or in combination with MK-801, a non-competitive NMDA receptor antagonist, and, in separate experiments, with scopolamine, a non-selective muscarinic antagonist. SB-269970 (10 mg/kg) significantly reversed the deficits induced by MK-801 (0.1 mg/kg) but augmented the deficit induced by scopolamine (0.06 mg/kg). The ability of SB-269970 to modulate MK-801-induced glutamate and dopamine extracellular levels was separately evaluated using biosensor technology and microdialysis in the prefrontal cortex of freely moving rats. SB-269970 normalized MK-801 -induced glutamate but not dopamine extracellular levels in the prefrontal cortex. Rat plasma and brain concentrations of MK-801 were not affected by co-administration of SB-269970, arguing for a pharmacodynamic rather than a pharmacokinetic mechanism. These results indicate that 5-HT₇ receptor antagonists might reverse cognitive deficits associated with NMDA receptor hypofunction by selectively normalizing glutamatergic neurotransmission.
5-HT₇ 受体在各种心境障碍动物模型中发挥作用；然而，其在认知中的功能仍在很大程度上存在推测。本研究评估了 5-HT₇ 受体选择性拮抗剂 SB-269970 在工作记忆缺陷的转化模型中的作用，并研究了其是否调节大鼠皮质谷氨酸和/或多巴胺神经传递。SB-269970 的作用在延迟非匹配位置任务中单独评估，或与 MK-801（非竞争性 NMDA 受体拮抗剂）联合评估，在单独的实验中，与东莨菪碱（非选择性毒蕈碱拮抗剂）联合评估。SB-269970（10mg/kg）显著逆转了 MK-801（0.1mg/kg）诱导的缺陷，但增强了东莨菪碱（0.06mg/kg）诱导的缺陷。使用生物传感器技术和微透析技术分别评估了 SB-269970 调节 MK-801 诱导的谷氨酸和多巴胺细胞外水平的能力，在自由活动大鼠的前额叶皮层中进行。SB-269970 使 MK-801 诱导的前额叶皮层谷氨酸正常化，但不使多巴胺细胞外水平正常化。SB-269970 共同给药并未影响 MK-801 的大鼠血浆和脑浓度，这表明是药效学机制而不是药代动力学机制。这些结果表明，5-HT₇ 受体拮抗剂可能通过选择性地调节谷氨酸能神经传递来逆转与 NMDA 受体功能低下相关的认知缺陷。
