Chronic administration of valproic acid reduces brain NMDA signaling via arachidonic acid in unanesthetized rats
Chronic administration of valproic acid reduces brain NMDA signaling via arachidonic acid in unanesthetized rats
复制标题
DOI：
10.1007/s11064-008-9700-2
复制
发表时间：
2008-11-01
影响因子：
4.4
通讯作者：
Rapoport, Stanley I.
中科院分区：
文献类型：
--
作者：
Basselin, Mireille;Chang, Lisa;Rapoport, Stanley I.
双相情感障碍患者大脑谷氨酸活性病理性升高的证据表明，情绪稳定剂部分通过下调谷氨酸活性来治疗该疾病。这种活性可能涉及第二信使花生四烯酸（AA，20:4n-6）。当刺激大鼠大脑中的谷氨酸 N-甲基-D-天冬氨酸 (NMDA) 受体并测量 AA 和相关反应时，我们用丙戊酸 (VPA) 测试了这一假设。将急性亚惊厥剂量的 NMDA (25 mg/kg i.p.) 或盐水给予已接受 i.p. 治疗的未麻醉大鼠。每天使用 VPA (200 mg/kg) 或载体，持续 30 天。静脉内 [1-C-14] AA 输注后进行定量放射自显影，用于对区域脑 AA 掺入系数 k*（AA 信号传导标记物）进行成像。在长期接受媒介物预处理的大鼠中，与生理盐水相比，NMDA 显着增加了 82 个检查大脑区域中 41 个区域的 k*，其中许多区域具有高 NMDA 受体密度，并且还增加了 AA 代谢物、前列腺素 E-2 (PGE(2)) 和血栓素 B-2 (TXB2) 的大脑浓度。 VPA 预处理降低了 PGE2 和 TXB2 的基线浓度，并阻止了 NMDA 诱导的 k* 和类二十烷酸浓度的增加。这些结果与卡马西平和锂也能阻断大鼠大脑中 NMDA 的 k* 反应的证据相结合，表明情绪稳定剂在双相情感障碍中的作用部分是通过下调涉及 AA 的谷氨酸能信号传导来实现的。
Evidence that brain glutamatergic activity is pathologically elevated in bipolar disorder suggests that mood stabilizers are therapeutic in the disease in part by downregulating glutamatergic activity. Such activity can involve the second messenger, arachidonic acid (AA, 20:4n-6). We tested this hypothesis with regard to valproic acid (VPA), when stimulating glutamatergic N-methyl-D-aspartate (NMDA) receptors in rat brain and measuring AA and related responses. An acute subconvulsant dose of NMDA (25 mg/kg i.p.) or saline was administered to unanesthetized rats that had been treated i.p. daily with VPA (200 mg/kg) or vehicle for 30 days. Quantitative autoradiography following intravenous [1-C-14] AA infusion was used to image regional brain AA incorporation coefficients k*, markers of AA signaling. In chronic vehicle-pretreated rats, NMDA compared with saline significantly increased k* in 41 of 82 examined brain regions, many of which have high NMDA receptor densities, and also increased brain concentrations of the AA metabolites, prostaglandin E-2 (PGE(2)) and thromboxane B-2 (TXB2). VPA pretreatment reduced baseline concentrations of PGE2 and TXB2, and blocked the NMDA induced increases in k* and in eicosanoid concentrations. These results, taken with evidence that carbamazepine and lithium also block k* responses to NMDA in rat brain, suggest that mood stabilizers act in bipolar disorder in part by downregulating glutamatergic signaling involving AA.