Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, 1-8-1 Inohana, Chiba, 260-8670, Japan.
Department of CNS Research, New Drug Research Division, Otsuka Pharmaceutical Co., Ltd., Tokushima, Japan.
Psychopharmacology (Berl). 2017 Nov;234(21):3165-3173. doi: 10.1007/s00213-017-4700-z. Epub 2017 Jul 26.
Brexpiprazole, a serotonin-dopamine activity modulator, is approved in the USA as an adjunctive therapy to antidepressants for treating major depressive disorders. Similar to the N-methyl-D-aspartate receptor (NMDAR) antagonist ketamine, the combination of brexpiprazole and fluoxetine has demonstrated antidepressant-like effects in animal models of depression.
The 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.
The 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.
A 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.
These 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.
布瑞哌唑是一种血清素-多巴胺活动调节剂，已获美国批准，作为抗抑郁药的辅助治疗药物，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，布瑞哌唑与氟西汀联合使用在抑郁症动物模型中显示出抗抑郁样作用。
本研究旨在探讨布瑞哌唑与氟西汀联合应用是否会影响与 NMDAR 神经传递相关的组织氨基酸水平[谷氨酸、谷氨酰胺、γ-氨基丁酸（GABA）、D-丝氨酸、L-丝氨酸和甘氨酸]。
单次[或重复（14 天）]口服给予载体、氟西汀（10mg/kg）、布瑞哌唑（0.1mg/kg）或两药联合后，检测前额皮质、纹状体、海马和小脑组织中的氨基酸水平。此外，我们还检测了单次给予 NMDAR 拮抗剂（R）-氯胺酮后氨基酸的组织水平。
单次给予氟西汀和布瑞哌唑联合用药显著增加了纹状体中的 GABA 水平、前额皮质中的 D-丝氨酸/L-丝氨酸比值和海马中的甘氨酸/L-丝氨酸比值。重复给予该联合用药显著改变了所有区域的氨基酸组织水平。有趣的是，重复给予该联合用药显著降低了前额皮质、纹状体和海马中的 D-丝氨酸/L-丝氨酸比值。相反，单次给予（R）-氯胺酮显著增加了前额皮质中的 D-丝氨酸/L-丝氨酸比值。
这些结果表明，这些氨基酸的组织水平的改变可能与布瑞哌唑和氟西汀联合应用的抗抑郁样作用有关。
