title: Betaine enhances antidepressant-like, but blocks psychotomimetic effects of ketamine in mice.
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.
authors.affiliation: Graduate Institute of Medical Sciences, National Defense Medical Center, 161, Section 6, Minquan East. Road., Neihu District, Taipei, 11453, Taiwan.
authors.forename: Jen-Cheng
authors.initials: JC
authors.lastname: Lin
authors.affiliation: Department of Pharmacology and Toxicology, Tzu Chi University, 701, Section 3, Chung-Yang Road, Hualien, 97004, Taiwan.
authors.forename: Mei-Yi
authors.initials: MY
authors.lastname: Lee
authors.affiliation: Institute of Neuroscience, National Chengchi University, 64, Sec. 2, ZhiNan Road, Wenshan District, Taipei City, 11605, Taiwan.|Research Center for Mind, Brain, and Learning, National Chengchi University, 64, Sec. 2, ZhiNan Road, Wenshan District, Taipei City, 11605, Taiwan.
authors.forename: Ming-Huan
authors.initials: MH
authors.lastname: Chan
authors.affiliation: Graduate Institute of Medical Sciences, National Defense Medical Center, 161, Section 6, Minquan East. Road., Neihu District, Taipei, 11453, Taiwan. yichyanc@gmail.com.|School of Medicine, Tzu Chi University, 701, Section 3, Chung-Yang Road, Hualien, 97004, Taiwan. yichyanc@gmail.com.|Department of Psychiatry, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, 289, Jianguo Road, Xindian District, New Taipei City, 23142, Taiwan. yichyanc@gmail.com.
authors.forename: Yi-Chyan
authors.initials: YC
authors.lastname: Chen
authors.affiliation: Graduate Institute of Medical Sciences, National Defense Medical Center, 161, Section 6, Minquan East. Road., Neihu District, Taipei, 11453, Taiwan. hwei@nhri.org.tw.|Department of Pharmacology and Toxicology, Tzu Chi University, 701, Section 3, Chung-Yang Road, Hualien, 97004, Taiwan. hwei@nhri.org.tw.|Institute of Neuroscience, National Chengchi University, 64, Sec. 2, ZhiNan Road, Wenshan District, Taipei City, 11605, Taiwan. hwei@nhri.org.tw.|Center for Neuropsychiatric Research, National Health Research Institutes, 35 Keyan Road, Zhunan, Miaoli County, 35053, Taiwan. hwei@nhri.org.tw.
authors.forename: Hwei-Hsien
authors.initials: HH
authors.lastname: Chen
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects*; D001622:Betaine / Q000494:pharmacology*; D003863:Depression; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D006213:Hallucinogens / Q000494:pharmacology*; D007649:Ketamine / Q000494:pharmacology*; D008297:Male; D051379:Mice; D065808:Prepulse Inhibition / Q000187:drug effects*; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists; D013550:Swimming
chemical_list: D000928:Antidepressive Agents; D018691:Excitatory Amino Acid Antagonists; D006213:Hallucinogens; D016194:Receptors, N-Methyl-D-Aspartate; D001622:Betaine; D007649:Ketamine
keywords: Behavior; Depression; NMDA receptor; Prepulse inhibition; Schizophrenia