Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, 1-8-1 Inohana, Chiba 260-8670, Japan.
Pharmacol Biochem Behav. 2012 Aug;102(2):329-34. doi: 10.1016/j.pbb.2012.05.007. Epub 2012 May 17.
Hyperactivity of the hypothalamic pituitary-adrenal (HPA) axis plays a role in the pathophysiology of major depressive disorder (MDD). Recent studies suggest the role of the glutamatergic system in the pathophysiology of MDD, and N-methyl-D-aspartate (NMDA) receptor antagonists have shown antidepressant effects in both preclinical and clinical studies. However, little is known about the role of adrenocorticotropic hormone (ACTH) specifically in the glutamatergic response to HPA axis activation. Glutamate is an NMDA receptor agonist, and glycine and D-serine act as co-agonists. Here, we measured brain concentrations of these amino acids in rats given repeated administration of ACTH (100 μg/rat/day, sc, for 14 days). Further, we also evaluated behavioral effects of memantine, a non-competitive NMDA antagonist, on immobility time in the forced swimming test and on locomotor activity in ACTH-treated rats. Compared with control rats, glutamine, glycine, L-serine, and D-serine levels were increased in the hippocampus of ACTH-treated rats; glutamate, glutamine, glycine, L-serine, and D-serine were increased in the cerebellum; and glutamine and glycine were increased in the frontal cortex and striatum, all with statistical significance. Remarkably, these increases in agonists and co-agonists might have led to the augmentation of NMDA receptor activity. ACTH treatment increased immobility time in the forced swimming test and decreased locomotor activity in rats. On the contrary, memantine (10 mg/kg, ip) significantly decreased immobility time in the forced swimming test and increased locomotor activity in ACTH-treated rats. Furthermore, imipramine (15 mg/kg, ip) did not alter immobility time in the forced swimming test whereas this drug significantly decreased locomotor activity in ACTH-treated rats. These results suggest that depressive-like behaviors by chronic ACTH treatment could be blocked by memantine.
下丘脑-垂体-肾上腺（HPA）轴的过度活跃在重度抑郁症（MDD）的病理生理学中发挥作用。最近的研究表明，谷氨酸能系统在 MDD 的病理生理学中起作用，N-甲基-D-天冬氨酸（NMDA）受体拮抗剂在临床前和临床研究中均显示出抗抑郁作用。然而，对于促肾上腺皮质激素（ACTH）在 HPA 轴激活的谷氨酸反应中的具体作用知之甚少。谷氨酸是 NMDA 受体激动剂，甘氨酸和 D-丝氨酸起协同激动剂作用。在这里，我们测量了给予反复给予 ACTH（100μg/大鼠/天，sc，14 天）的大鼠脑中这些氨基酸的浓度。此外，我们还评估了非竞争性 NMDA 拮抗剂美金刚对 ACTH 处理大鼠强迫游泳试验中不动时间和运动活性的行为影响。与对照大鼠相比，ACTH 处理大鼠的海马中谷氨酰胺、甘氨酸、L-丝氨酸和 D-丝氨酸水平升高；小脑中谷氨酸、谷氨酰胺、甘氨酸、L-丝氨酸和 D-丝氨酸水平升高；前额叶皮层和纹状体中谷氨酰胺和甘氨酸水平升高，均具有统计学意义。值得注意的是，这些激动剂和协同激动剂的增加可能导致 NMDA 受体活性增强。ACTH 处理增加了强迫游泳试验中的不动时间并降低了大鼠的运动活性。相反，美金刚（10mg/kg，ip）显著降低了强迫游泳试验中的不动时间并增加了 ACTH 处理大鼠的运动活性。此外，丙咪嗪（15mg/kg，ip）没有改变强迫游泳试验中的不动时间，而这种药物显著降低了 ACTH 处理大鼠的运动活性。这些结果表明，慢性 ACTH 处理引起的抑郁样行为可被美金刚阻断。
