Journal
NEUROPHARMACOLOGY
Volume 126, Issue -, Pages 121-127Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.neuropharm.2017.08.038
Keywords
Methoxetamine; Ketamine; Depression; Antidepressant; AMPA receptor; Serotonergic system
Categories
Funding
- National Research Foundation in Korea [2017M3A9G2051240, 2016R1D1A1B02010387, 2017R1D1A-1A02018695]
- National Research Foundation of Korea [2017M3A9G2051240, 2016R1D1A1B02010387] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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Depression afflicts around 16% of the world's population, making it one of the leading causes of disease burden worldwide. Despite a number of antidepressants available today, the delayed onset time and low remission rate of these treatments are still a major challenge. The N-methyl-D-aspartate (NMDA) receptor antagonist ketamine has shown to produce rapid and sustained antidepressant effects and has paved the way for a new generation of glutamate-based antidepressants. Methoxetamine (MXE) is a ketamine analogue that acts as an NMDA receptor antagonist and a serotonin reuptake inhibitor. However, no studies have evaluated the antidepressant effects of MXE. Here, we assessed whether MXE produces antidepressant effects and explored possible mechanisms underlying its effects. Mice were treated with MXE (2.5, 5, or 10 mg/kg) and their behavior was evaluated 30 min and 24 h later in an array of behavioral experiments used for screening antidepressant drugs. A separate group of mice were treated with NBQX, an alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist, or ketanserin, a 5HT2 receptor antagonist, before MXE (5 mg/kg) administration in the forced swimming test (FST). We also investigated the effect of MXE on glutamatergic- and serotonergic-related genes in the mouse hippocampus using quantitative real-time PCR. MXE produced antidepressant effects 30 min after treatment that persisted for 24 h. Both NBQX and ketanserin blocked the antidepressant effects of MXE in the FST. MXE also altered hippocampal glutamatergic- and serotonergic gene expressions. These results suggest that MXE has rapid and sustained antidepressant effects, possibly mediated by the glutamatergic and serotonergic system. (C) 2017 Elsevier Ltd. All rights reserved.
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