Phencyclidine-induced cognitive deficits in mice are improved by subsequent subchronic administration of the novel selective α7 nicotinic receptor agonist SSR180711
Phencyclidine-induced cognitive deficits in mice are improved by subsequent subchronic administration of the novel selective α7 nicotinic receptor agonist SSR180711
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DOI：
10.1016/j.biopsych.2007.04.034
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发表时间：
2008-01-01
影响因子：
10.6
通讯作者：
Iyo, Masaomi
中科院分区：
文献类型：
--
作者：
Hashimoto, Kenji;Ishima, Tamaki;Iyo, Masaomi
背景资料：越来越多的证据表明，α 7烟碱受体（α 7 nAChR）激动剂可能是精神分裂症认知缺陷的潜在治疗药物。本研究旨在探讨新型选择性α 7 nAChR激动剂SSR 180711对重复给予N-甲基-D-天冬氨酸受体拮抗剂苯环己哌啶（PCP）后小鼠认知功能障碍的影响。随后，连续2周IP给予溶媒、SSR 180711（0.3或3.0 mg/kg/天）、SSR 180711（3.0 mg/kg/天）+选择性α 7 nAChR拮抗剂甲基乌头碱（MLA; 3.0 mg/kg/天）或MLA（3.0 mg/kg/天）。结果：SSR 180711（3.0 mg/kg）亚慢性（2周）给药可显著改善PCP诱导的认知功能障碍。SSR 180711（3.0 mg/kg）的作用被MLA（3.0 mg/kg）联合给药显著拮抗。此外，蛋白质印迹分析和免疫组织化学显示，PCP的额叶皮质和海马中的α 7 nAChRs水平（10 mg/kg/天，持续10天）治疗的小鼠的存活率显著低于盐水治疗的小鼠。这些发现表明，重复PCP给药显著降低了大脑中α 7 nAChR的密度，α 7 nAChR激动剂SSR 180711可改善PCP重复给药后小鼠的认知障碍。因此，包括SSR 180711在内的α 7 nAChR激动剂是治疗精神分裂症患者认知缺陷的潜在治疗药物。
Background: Accumulating evidence suggests that alpha 7 nicotinic receptor (alpha 7 nAChR) agonists could be potential therapeutic drugs for cognitive deficits in schizophrenia. The present study was undertaken to examine the effects of the novel selective alpha 7 nAChR agonist SSR180711 on cognitive deficits in mice after repeated administration of the N-methyl-D-aspartate receptor antagonist phencyclidine (PCP).Methods: Saline or PCP (10 mg/kg/day for 10 days) was administered to mice. Subsequently, vehicle, SSR180711 (.3 or 3.0 mg/kg/day), SSR180711 (3.0 mg/kg/day) + the selective alpha 7 nAChR antagonist methyllycaconitine (MLA; 3.0 mg/kg/day), or MLA (3.0 mg/kg/day) was administered IP for 2 consecutive weeks. Twenty-four hours after the final administration, a novel object recognition test was performed.Results: The PCP-induced cognitive deficits were significantly improved by subsequent subchronic (2-week) administration of SSR180711 (3.0 mg/kg). The effects of SSR180711 (3.0 mg/kg) were significantly antagonized by co-administration of MLA (3.0 mg/kg). Furthermore, Western blot analysis and immunohistochemistry revealed that levels of alpha 7 nAChRs in the frontal cortex and hippocampus of the PCP (10 mg/kg/day for 10 days)-treated mice were significantly lower than those of saline-treated mice.Conclusions: These findings suggest that repeated PCP administration significantly decreased the density of alpha 7 nAChRs in the brain and that the alpha 7 nAChR agonist SSR180711 could ameliorate cognitive deficits in mice after repeated administration of PCP. Therefore, alpha 7 nAChR agonists including SSR180711 are potential therapeutic drugs for treating cognitive deficits in schizophrenic patients.