Du Jing, Suzuki Katsuji, Wei Yanling, Wang Yun, Blumenthal Rayah, Chen Zheng, Falke Cynthia, Zarate Carlos A, Manji Husseini K
Laboratory of Molecular Pathophysiology, Mood and Anxiety Disorders Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892, USA.
Neuropsychopharmacology. 2007 Apr;32(4):793-802. doi: 10.1038/sj.npp.1301178. Epub 2006 Aug 16.
A growing body of data suggests that the glutamatergic system may be involved in the pathophysiology and treatment of severe mood disorders. Chronic treatment with the antimanic agents, lithium and valproate, resulted in reduced synaptic expression of the AMPA(-amino-3-hydroxy-5-methylisoxazole-4-propionic acid) receptor subunit GluR1 in the hippocampus, while treatment with an antidepressant (imipramine) enhanced the synaptic expression of GluR1. The anticonvulsants, lamotrigine (6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine) and riluzole (2-amino-6-trifluoromethoxybenzothiazole), have been demonstrated to have efficacy in the depressive phase of bipolar disorder. We therefore sought to determine the role of these anticonvulsants, compared to that of the predominantly antimanic anticonvulsant valproate, on AMPA receptor localization. We found that the agents with a predominantly antidepressant profile, namely lamotrigine and riluzole, significantly enhanced the surface expression of GluR1 and GluR2 in a time- and dose-dependent manner in cultured hippocampal neurons. By contrast, the predominantly antimanic agent, valproate, significantly reduced surface expression of GluR1 and GluR2. Concomitant with the GluR1 and GluR2 changes, the peak value of depolarized membrane potential evoked by AMPA was significantly higher in lamotrigine- and riluzole-treated neurons, supporting the surface receptor changes. Phosphorylation of GluR1 at the PKA (cAMP-dependent protein kinase) site (S845) was enhanced in both lamotrigine- and riluzole-treated hippocampal neurons, but reduced in valproate-treated neurons. In addition, lamotrigine and riluzole, as well as the traditional antidepressant imipramine, also increased GluR1 phosphorylation at GluR1 (S845) in the hippocampus after chronic in vivo treatment. Our findings suggest that regulation of GluR1/2 surface levels and function may be responsible for the different clinical profile of anticonvulsants (antimanic or antidepressant), and may suggest avenues for the development of novel therapeutics for these illnesses.
越来越多的数据表明，谷氨酸能系统可能参与严重情绪障碍的病理生理学过程及治疗。用抗躁狂药物锂盐和丙戊酸盐进行长期治疗，会导致海马体中AMPA（α-氨基-3-羟基-5-甲基异恶唑-4-丙酸）受体亚基GluR1的突触表达降低，而用抗抑郁药（丙咪嗪）治疗则会增强GluR1的突触表达。抗惊厥药拉莫三嗪（6-(2,3-二氯苯基)-1,2,4-三嗪-3,5-二胺）和利鲁唑（2-氨基-6-三氟甲氧基苯并噻唑）已被证明在双相情感障碍的抑郁期有效。因此，我们试图确定与主要的抗躁狂抗惊厥药丙戊酸盐相比，这些抗惊厥药对AMPA受体定位的作用。我们发现，主要具有抗抑郁作用的药物，即拉莫三嗪和利鲁唑，在培养的海马神经元中以时间和剂量依赖的方式显著增强了GluR1和GluR2的表面表达。相比之下，主要的抗躁狂药物丙戊酸盐则显著降低了GluR1和GluR2的表面表达。与GluR1和GluR2的变化相一致，在拉莫三嗪和利鲁唑处理的神经元中，由AMPA诱发的去极化膜电位峰值显著更高，这支持了表面受体的变化。在拉莫三嗪和利鲁唑处理的海马神经元中，GluR1在PKA（环磷酸腺苷依赖性蛋白激酶）位点（S845）的磷酸化增强，但在丙戊酸盐处理的神经元中则降低。此外，在长期体内治疗后，拉莫三嗪、利鲁唑以及传统抗抑郁药丙咪嗪也增加了海马体中GluR1在GluR1（S845）位点的磷酸化。我们的研究结果表明，GluR1/2表面水平和功能的调节可能是抗惊厥药（抗躁狂或抗抑郁）不同临床特征的原因，并可能为这些疾病的新型治疗方法的开发提供途径。
