Phosphodiesterase 2A Inhibitor TAK-915 Ameliorates Cognitive Impairments and Social Withdrawal in N-Methyl-d-Aspartate Receptor Antagonist–Induced Rat Models of Schizophrenia
| العنوان: | Phosphodiesterase 2A Inhibitor TAK-915 Ameliorates Cognitive Impairments and Social Withdrawal in N-Methyl-d-Aspartate Receptor Antagonist–Induced Rat Models of Schizophrenia |
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| المؤلفون: | Takahiko Taniguchi, Yuki Ito, Haruka Imada, Masato Nakashima, Hiroki Iwashita, Noriko Suzuki, Eri Shiraishi, Maki Miyamoto |
| المصدر: | Journal of Pharmacology and Experimental Therapeutics. 365:179-188 |
| بيانات النشر: | American Society for Pharmacology & Experimental Therapeutics (ASPET), 2018. |
| سنة النشر: | 2018 |
| مصطلحات موضوعية: | 0301 basic medicine, Pharmacology, Radial arm maze, medicine.drug_class, Chemistry, Hippocampus, Phosphodiesterase, Striatum, Receptor antagonist, 03 medical and health sciences, Glutamatergic, 030104 developmental biology, 0302 clinical medicine, medicine, Molecular Medicine, NMDA receptor, Receptor, 030217 neurology & neurosurgery |
| الوصف: | The pathophysiology of schizophrenia has been associated with glutamatergic dysfunction. Modulation of the glutamatergic signaling pathway, including N-methyl-d-aspartate (NMDA) receptors, can provide a new therapeutic target for schizophrenia. Phosphodiesterase 2A (PDE2A) is highly expressed in the forebrain, and is a dual substrate enzyme that hydrolyzes both cAMP and cGMP, which play pivotal roles as intracellular second messengers downstream of NMDA receptors. Here we characterize the in vivo pharmacological profile of a selective and brain-penetrant PDE2A inhibitor, (N-{(1S)-1-[3-fluoro-4-(trifluoromethoxy)phenyl]-2-methoxyethyl}-7-methoxy-2-oxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-carboxamide) (TAK-915) as a novel treatment of schizophrenia. Oral administration of TAK-915 at 3 and 10 mg/kg significantly increased cGMP levels in the frontal cortex, hippocampus, and striatum of rats. TAK-915 at 10 mg/kg significantly upregulated the phosphorylation of α-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid receptor subunit GluR1 in the rat hippocampus. TAK-915 at 3 and 10 mg/kg significantly attenuated episodic memory deficits induced by the NMDA receptor antagonist (+)-MK-801 hydrogen maleate (MK-801) in the rat passive avoidance test. TAK-915 at 10 mg/kg significantly attenuated working memory deficits induced by MK-801 in the rat radial arm maze test. Additionally, TAK-915 at 10 mg/kg prevented subchronic phencyclidine-induced social withdrawal in social interaction in rats. In contrast, TAK-915 did not produce antipsychotic-like activity; TAK-915 had little effect on MK-801- or methamphetamine-induced hyperlocomotion in rats. These results suggest that TAK-915 has a potential to ameliorate cognitive impairments and social withdrawal in schizophrenia. |
| تدمد: | 1521-0103 0022-3565 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_________::45ca9abdeb26f084b89cb07e917608f6 https://doi.org/10.1124/jpet.117.245506 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi...........45ca9abdeb26f084b89cb07e917608f6 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15210103 00223565 |
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