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Betaine enhances antidepressant-like, but blocks psychotomimetic effects of ketamine in mice

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Abstract

Ketamine is emerging as a new hope against depression, but ketamine-associated psychotomimetic effects limit its clinical use. An adjunct therapy along with ketamine to alleviate its adverse effects and even potentiate the antidepressant effects might be an alternative strategy. Betaine, a methyl derivative of glycine and a dietary supplement, has been shown to have antidepressant-like effects and to act like a partial agonist at the glycine site of N-methyl-D-aspartate receptors (NMDARs). Accordingly, betaine might have potential to be an adjunct to ketamine treatment for depression. The antidepressant-like effects of ketamine and betaine were evaluated by forced swimming test and novelty suppressed feeding test in mice. Both betaine and ketamine produced antidepressant-like effects. Furthermore, we determined the effects of betaine on ketamine-induced antidepressant-like and psychotomimetic behaviors, motor incoordination, hyperlocomotor activity, and anesthesia. The antidepressant-like responses to betaine combined with ketamine were stronger than their individual effects. In contrast, ketamine-induced impairments in prepulse inhibition, novel object recognition test, social interaction, and rotarod test were remarkably attenuated, whereas ketamine-induced hyperlocomotion and loss of righting reflex were not affected by betaine. These findings revealed that betaine could enhance the antidepressant-like effects, yet block the psychotomimetic effects of ketamine, suggesting that betaine can be considered as an add-on therapy to ketamine for treatment-resistant depression and suitable for the treatment of depressive symptoms in patients with schizophrenia.

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Acknowledgments

This work was supported by the National Health Research Institutes (NP-103-PP-02) and the Ministry of Science and Technology (MOST-104-2314-B-400-007-MY22).

Authors’ contributions

MHC, YCC, and HHC were responsible for the study concept and design. JCL and MYL contributed to the acquisition and analysis of the animal data and interpretation of the findings. JCL drafted the manuscript. YCC and HHC provided critical revision of the manuscript for important intellectual content. MHC contributed to reviewing and editing of the manuscript. All of the authors critically reviewed the content and approved the final version for publication.

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Authors and Affiliations

  1. Graduate Institute of Medical Sciences, National Defense Medical Center, 161, Section 6, Minquan East. Road., Neihu District, Taipei, 11453, Taiwan

    Jen-Cheng Lin, Yi-Chyan Chen & Hwei-Hsien Chen

  2. Department of Pharmacology and Toxicology, Tzu Chi University, 701, Section 3, Chung-Yang Road, Hualien, 97004, Taiwan

    Mei-Yi Lee & Hwei-Hsien Chen

  3. School of Medicine, Tzu Chi University, 701, Section 3, Chung-Yang Road, Hualien, 97004, Taiwan

    Yi-Chyan Chen

  4. Institute of Neuroscience, National Chengchi University, 64, Sec. 2, ZhiNan Road, Wenshan District, Taipei City, 11605, Taiwan

    Ming-Huan Chan & Hwei-Hsien Chen

  5. Research Center for Mind, Brain, and Learning, National Chengchi University, 64, Sec. 2, ZhiNan Road, Wenshan District, Taipei City, 11605, Taiwan

    Ming-Huan Chan

  6. Department of Psychiatry, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, 289, Jianguo Road, Xindian District, New Taipei City, 23142, Taiwan

    Yi-Chyan Chen

  7. Center for Neuropsychiatric Research, National Health Research Institutes, 35 Keyan Road, Zhunan, Miaoli County, 35053, Taiwan

    Hwei-Hsien Chen

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  1. Jen-Cheng Lin
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Supplementary Fig. S1

NMDAR glycine binding site antagonist 7-chlorokynurenic acid (7-CTKA) abolished the reversing effect of betaine on ketamine-induced cognitive deficits in the novel object recognition test. 7-CTKA (0, 0.3 and 1 mg/kg, i.p.) was given 30 min prior to betaine (30 mg/kg, i.p.) or saline, followed by administration of ketamine (30 mg/kg) or saline 30 min later. The training session was conducted 5 min after ketamine administration. The retention session was performed 24 h later. All values are expressed as the mean ± SEM. A mixed-design ANOVA revealed significant main effects of treatment (F5, 43 = 4.361, p < 0.01) and session (F1, 43 = 47.944, p < 0.001) and a significant treatment x session interaction (F5, 43 = 8.677, p < 0.001). 7-CTKA (1 mg/kg, i.p.) affected the novel object preferences and disrupted the reversing effect of betaine on ketamine-induced impairment in the retention session. ***p < 0.001 vs. Saline/Saline/Saline, ## p < 0.01, ### p < 0.001 vs. Saline/Saline /Ketamine, $$$ p < 0.001 vs. Saline /Betaine/Ketamine. (PPTX 110 kb)

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Lin, JC., Lee, MY., Chan, MH. et al. Betaine enhances antidepressant-like, but blocks psychotomimetic effects of ketamine in mice. Psychopharmacology 233, 3223–3235 (2016). https://doi.org/10.1007/s00213-016-4359-x

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  • DOI: https://doi.org/10.1007/s00213-016-4359-x

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