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Alterations in amino acid levels in mouse brain regions after adjunctive treatment of brexpiprazole with fluoxetine: comparison with (R)-ketamine

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Abstract

Rationale

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.

Objectives

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.

Methods

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.

Results

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.

Conclusions

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.

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Acknowledgements

This study was supported by Otsuka Pharmaceutical Co., Ltd. (Tokyo, Japan), and the Strategic Research Program for Brain Sciences from Japan Agency for Medical Research and Development, AMED (to K.H.). Ms. Min Ma was supported by the Nurture of Creative Research Leaders in Immune System Regulation and Innovative Therapeutics Program of Chiba University. Dr. Qian Ren and Dr. Chun Yang were supported by Research Fellowship of the Japan Society for the Promotion of Science (Tokyo, Japan). Dr. Chao Dong was supported by the Uehara Research Foundation (Tokyo, Japan).

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Author notes

  1. Min Ma and Qian Ren have equal contribution.

Authors and Affiliations

  1. Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, 1-8-1 Inohana, Chiba, 260-8670, Japan

    Min Ma, Qian Ren, Yuko Fujita, Chun Yang, Chao Dong & Kenji Hashimoto

  2. Department of CNS Research, New Drug Research Division, Otsuka Pharmaceutical Co., Ltd., Tokushima, Japan

    Yuta Ohgi & Takashi Futamura

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  1. Min Ma
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  2. Qian Ren
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  3. Yuko Fujita
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  4. Chun Yang
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  5. Chao Dong
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  6. Yuta Ohgi
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  7. Takashi Futamura
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  8. Kenji Hashimoto
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Corresponding author

Correspondence to Kenji Hashimoto.

Ethics declarations

The study was approved by the Animal Care and Use Committee of Chiba University Graduate School of Medicine.

Conflict of interest

Dr. Hashimoto is an inventor on a filed patent application on “The use of R-ketamine in the treatment of psychiatric diseases” by Chiba University. Dr. Hashimoto received research support from Dainippon-Sumitomo, Mochida, Otsuka, and Taisho. Dr. Ohgi and Dr. Futamura are employees of Otsuka Pharmaceutical Co., Ltd. (Tokyo, Japan). Other authors declare no conflict of interest.

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Ma, M., Ren, Q., Fujita, Y. et al. Alterations in amino acid levels in mouse brain regions after adjunctive treatment of brexpiprazole with fluoxetine: comparison with (R)-ketamine. Psychopharmacology 234, 3165–3173 (2017). https://doi.org/10.1007/s00213-017-4700-z

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  • DOI: https://doi.org/10.1007/s00213-017-4700-z

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