Discovery Pharmacology I, Molecular Function and Pharmacology Laboratories, Taisho Pharmaceutical Co., Ltd., 1-403 Yoshino-cho, Kita-ku, Saitama, Saitama 331-9530, Japan.
Discovery Pharmacology I, Molecular Function and Pharmacology Laboratories, Taisho Pharmaceutical Co., Ltd., 1-403 Yoshino-cho, Kita-ku, Saitama, Saitama 331-9530, Japan.
Neurosci Lett. 2014 May 1;567:30-4. doi: 10.1016/j.neulet.2014.03.025. Epub 2014 Mar 27.
Abnormalities in electroencephalogram gamma oscillations have been implicated in schizophrenic symptoms. N-methyl-d-aspartate (NMDA) receptor antagonists produce behavioral abnormalities that are similar to the symptoms of schizophrenia, including social and cognitive impairment, and also increase the power of spontaneous gamma oscillations in the frontal cortex in rodents. Both mGlu2/3 receptor agonists and mGlu1 receptor antagonists reportedly improve behavioral abnormalities elicited by NMDA receptor antagonists in rodents. The present study evaluated the effects of an mGlu2/3 receptor agonist and an mGlu1 receptor antagonist on aberrant basal gamma oscillations elicited by an NMDA receptor antagonist, ketamine, in the rat frontal cortex. Ketamine increased spontaneous cortical gamma oscillations. Pretreatment with an mGlu2/3 receptor agonist, (-)-2-oxa-4-aminobicyclo[3.1.0]hexane-4,6-dicarboxylate (LY379268), or an mGlu1 receptor antagonist, (3,4-dihydro-2H-pyrano[2,3-b]quinolin-7-yl)-(cis-4-methoxycyclohexyl)-methanone (JNJ16259685), reduced the ketamine-induced basal gamma hyperactivity. These findings indicate that the stimulation of mGlu2/3 receptors and the inhibition of mGlu1 receptors reverse aberrant gamma oscillations, and these effects may partially explain the antipsychotic-like properties of mGlu2/3 receptor agonists and mGlu1 receptor antagonists.
异常的脑电图γ振荡已被牵连到精神分裂症的症状中。N-甲基-D-天冬氨酸（NMDA）受体拮抗剂产生类似于精神分裂症的行为异常，包括社交和认知障碍，并且还增加了啮齿动物额皮质中自发性γ振荡的功率。据报道，mGlu2/3 受体激动剂和 mGlu1 受体拮抗剂可改善 NMDA 受体拮抗剂在啮齿动物中引起的行为异常。本研究评估了 mGlu2/3 受体激动剂和 mGlu1 受体拮抗剂对 NMDA 受体拮抗剂氯胺酮在大鼠前额皮质中引起的异常基础γ振荡的影响。氯胺酮增加了自发性皮质γ振荡。用 mGlu2/3 受体激动剂(-)-2-氧代-4-氨基双环[3.1.0]己烷-4,6-二羧酸酯（LY379268）或 mGlu1 受体拮抗剂（3,4-二氢-2H-吡喃[2,3-b]喹啉-7-基）-（顺式-4-甲氧基环己基）-甲酮（JNJ16259685）预处理可减少氯胺酮引起的基础γ过度活动。这些发现表明，mGlu2/3 受体的刺激和 mGlu1 受体的抑制可逆转异常的γ振荡，这些作用可能部分解释了 mGlu2/3 受体激动剂和 mGlu1 受体拮抗剂的抗精神病特性。
