Alterations in amino acid levels in mouse brain regions after adjunctive treatment of brexpiprazole with fluoxetine: comparison with (R)-ketamine
Alterations in amino acid levels in mouse brain regions after adjunctive treatment of brexpiprazole with fluoxetine: comparison with (R)-ketamine
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DOI：
10.1007/s00213-017-4700-z
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发表时间：
2017-07
影响因子：
3.4
通讯作者：
M. Ma;Q. Ren;Yuko Fujita;Chun Yang;C. Dong;Y. Ohgi;T. Futamura;K. Hashimoto
中科院分区：
文献类型：
--
作者：
M. Ma;Q. Ren;Yuko Fujita;Chun Yang;C. Dong;Y. Ohgi;T. Futamura;K. Hashimoto
基本原理Brexpiprzo 是一种血清素-多巴胺活性调节剂，在美国被批准作为抗抑郁药的辅助疗法，用于治疗重度抑郁症。与N-甲基-D-天冬氨酸受体（NMDAR）拮抗剂氯胺酮类似，布瑞哌唑和氟西汀的组合在抑郁症动物模型中显示出抗抑郁样作用。 目的本研究旨在探讨布瑞哌唑和氟西汀的组合是否会影响氨基酸[谷氨酸、谷氨酰胺、 与 NMDAR 神经传递相关的 γ-氨基丁酸 (GABA)、D-丝氨酸、L-丝氨酸和甘氨酸]。方法单次[或重复（14 天）]口服载体、氟西汀（10 mg/kg）、 布瑞哌唑（0.1 毫克/千克），或两种药物的组合。此外，我们还测量了单次施用 NMDAR 拮抗剂 (R)-氯胺酮后的组织氨基酸水平。 结果单次注射氟西汀和布瑞哌唑组合可显着增加纹状体中的 GABA 水平、额叶皮层中的 D-丝氨酸/L-丝氨酸比率以及海马中的甘氨酸/L-丝氨酸比率。重复施用该组合显着改变了所有区域的氨基酸组织水平。有趣的是，重复施用该组合显着降低了额叶皮层、纹状体和海马中的 D-丝氨酸/L-丝氨酸比率。相比之下，单次施用 (R)-氯胺酮可显着增加额叶皮层中的 D-丝氨酸/L-丝氨酸比率。 结论这些结果表明，这些氨基酸的组织水平的改变可能与 brexpiprmaze 和氟西汀组合的抗抑郁样作用有关。
RationaleBrexpiprazole, a serotonin–dopamine activity modulator, is approved in the USA as an adjunctive therapy to antidepressants for treating major depressive disorders. Similar to theN-methyl-D-aspartate receptor (NMDAR) antagonist ketamine, the combination of brexpiprazole and fluoxetine has demonstrated antidepressant-like effects in animal models of depression.ObjectivesThe present study was conducted to examine whether the combination of brexpiprazole and fluoxetine could affect the tissue levels of amino acids [glutamate, glutamine, γ-aminobutyric acid (GABA), D-serine, L-serine, and glycine] that are associated with NMDAR neurotransmission.MethodsThe tissue levels of amino acids in the frontal cortex, striatum, hippocampus, and cerebellum were measured after a single [or repeated (14 days)] oral administration of vehicle, fluoxetine (10 mg/kg), brexpiprazole (0.1 mg/kg), or a combination of the two drugs. Furthermore, we measured the tissue levels of amino acids after a single administration of the NMDAR antagonist (R)-ketamine.ResultsA single injection of the combination of fluoxetine and brexpiprazole significantly increased GABA levels in the striatum, the D-serine/L-serine ratio in the frontal cortex, and the glycine/L-serine ratio in the hippocampus. A repeated administration of the combination significantly altered the tissue levels of amino acids in all regions. Interestingly, a repeated administration of the combination significantly decreased the D-serine/L-serine ratio in the frontal cortex, striatum, and hippocampus. In contrast, a single administration of (R)-ketamine significantly increased the D-serine/L-serine ratio in the frontal cortex.ConclusionsThese results suggested that alterations in the tissue levels of these amino acids may be involved in the antidepressant-like effects of the combination of brexpiprazole and fluoxetine.