Basselin Mireille, Villacreses Nelly E, Chen Mei, Bell Jane M, Rapoport Stanley I
Brain Physiology and Metabolism Section, National Institute on Aging, National Institutes of Health, Bethesda, Maryland 20892, USA.
Biol Psychiatry. 2007 Oct 15;62(8):934-43. doi: 10.1016/j.biopsych.2007.04.021. Epub 2007 Jul 12.
Lithium and carbamazepine (CBZ) are used to treat mania in bipolar disorder. When given chronically to rats, both agents reduce arachidonic acid (AA) turnover in brain phospholipids and downstream AA metabolism. Lithium in rats also attenuates brain N-methyl-D-aspartic acid receptor (NMDAR) signaling via AA. We hypothesized that, like chronic lithium, chronic CBZ administration to rats would reduce NMDAR-mediated signaling via AA.
We used our fatty acid method with quantitative autoradiography to image the regional brain incorporation coefficient k* of AA, a marker of AA signaling, in unanesthetized rats that had been given 25 mg/kg/day I.P. CBZ or vehicle for 30 days, then injected with NMDA (25 mg/kg I.P.) or saline. We also measured brain concentrations of two AA metabolites, prostaglandin E(2) (PGE(2)) and thromboxane B(2) (TXB(2)).
In chronic vehicle-treated rats, NMDA compared with saline increased k* significantly in 69 of 82 brain regions examined, but did not change k* significantly in any region in CBZ-treated rats. In vehicle- but not CBZ-treated rats, NMDA also increased brain concentrations of PGE(2) and TXB(2).
Chronic CBZ administration to rats blocks increments in the AA signal k*, and in PGE(2) and TXB(2) concentrations that are produced by NMDA in vehicle-treated rats. The clinical action of antimanic drugs might involve inhibition of brain NMDAR-mediated signaling involving AA and its metabolites.
锂盐和卡马西平（CBZ）用于治疗双相情感障碍中的躁狂发作。长期给予大鼠这两种药物时，它们都会降低脑磷脂中花生四烯酸（AA）的周转率以及AA的下游代谢。大鼠体内的锂盐还会通过AA减弱脑N-甲基-D-天冬氨酸受体（NMDAR）信号传导。我们推测，与慢性给予锂盐一样，慢性给予大鼠CBZ会降低通过AA介导的NMDAR信号传导。
我们采用脂肪酸方法结合定量放射自显影技术，对未麻醉的大鼠脑内AA的区域掺入系数k进行成像，k是AA信号的一个标志物。这些大鼠腹腔注射25mg/kg/天的CBZ或赋形剂，持续30天，然后注射N-甲基-D-天冬氨酸（NMDA，25mg/kg腹腔注射）或生理盐水。我们还测量了两种AA代谢产物前列腺素E2（PGE2）和血栓素B2（TXB2）的脑内浓度。
在慢性给予赋形剂的大鼠中，与注射生理盐水相比，NMDA使82个检测脑区中的69个脑区的k显著增加，但在给予CBZ的大鼠中，任何脑区的k均无显著变化。在给予赋形剂而非CBZ的大鼠中，NMDA还增加了脑内PGE2和TXB2的浓度。
慢性给予大鼠CBZ可阻断NMDA在给予赋形剂的大鼠中所产生的AA信号k*以及PGE2和TXB2浓度的增加。抗躁狂药物的临床作用可能涉及抑制脑内由AA及其代谢产物介导的NMDAR信号传导。
