Erciyes University, Faculty of Pharmacy, Department of Pharmacology, Kayseri, Turkey.
Marmara University, School of Medicine, Department of Embryology and Histology, Istanbul, Turkey.
Behav Brain Res. 2021 Jan 15;397:112946. doi: 10.1016/j.bbr.2020.112946. Epub 2020 Oct 1.
The majority of schizophrenia patients have cognitive deficits as a separate symptom cluster independent of positive or negative symptoms. Current medicines, unfortunately, cannot provide clear benefits for cognitive symptoms in patients. Recent findings showed decreased α7 nicotinic acetylcholine receptor (nAChR) expressions in subjects with schizophrenia. α7 nAChR full/partial agonists and positive allosteric modulators (PAMs) may be valuable drug candidates to treat cognitive deficits of disease. This study comparatively investigated the effect of α7 nAChR agonist (A-582941), type I PAM (CCMI), type II PAM (PNU-120596), and the antipsychotic drug (clozapine) on behavioral, molecular, and immunohistochemical parameters in a subchronic MK-801 model of schizophrenia in male rats. Novel object recognition (NOR) and Morris water maze (MWM) tests were performed to evaluate recognition and spatial memories, respectively. Gene and protein expressions of parvalbumin, glutamic acid decarboxylase-67 (GAD67), and α7 nAChR were examined in the rats' hippocampal tissue. The subchronic MK-801 administration produced cognitive deficits in the NOR and MWM tests. It also decreased the protein and gene expressions of parvalbumin, GAD67, and α7 nAChR in the hippocampus. Clozapine, A-582941, and PNU-120596 but not CCMI increased the parvalbumin and α7 nAChR expressions and provided benefits in recognition memory. Interestingly, clozapine and CCMI restored the MK-801 induced deficits on GAD1 expression and spatial memory while A-582941 and PNU-120596 were ineffective. These results indicated that α7 nAChR agonist, type I and type II PAMs may provide benefits in different types of cognitive deficits rather than a complete treatment in schizophrenia.
大多数精神分裂症患者存在认知缺陷，作为一种独立的症状群，与阳性或阴性症状无关。不幸的是，目前的药物并不能为患者的认知症状带来明显的益处。最近的研究发现，精神分裂症患者的α7 烟碱型乙酰胆碱受体（nAChR）表达水平降低。α7 nAChR 全/部分激动剂和正变构调节剂（PAMs）可能是治疗疾病认知缺陷的有价值的候选药物。本研究比较了 α7 nAChR 激动剂（A-582941）、I 型 PAM（CCMI）、II 型 PAM（PNU-120596）和抗精神病药物（氯氮平）对雄性大鼠亚慢性 MK-801 精神分裂症模型的行为、分子和免疫组织化学参数的影响。新物体识别（NOR）和 Morris 水迷宫（MWM）测试分别用于评估识别和空间记忆。检测了大鼠海马组织中 parvalbumin、谷氨酸脱羧酶-67（GAD67）和α7 nAChR 的基因和蛋白表达。亚慢性 MK-801 给药导致 NOR 和 MWM 测试中的认知缺陷。它还降低了海马中 parvalbumin、GAD67 和α7 nAChR 的蛋白和基因表达。氯氮平、A-582941 和 PNU-120596 但不是 CCMI 增加了 parvalbumin 和 α7 nAChR 的表达，并改善了识别记忆。有趣的是，氯氮平和 CCMI 恢复了 MK-801 诱导的 GAD1 表达和空间记忆缺陷，而 A-582941 和 PNU-120596 则无效。这些结果表明，α7 nAChR 激动剂、I 型和 II 型 PAMs 可能对不同类型的认知缺陷有益，而不是对精神分裂症的全面治疗。
