Abstract
Ketamine (KET) is an N-methyl-D-aspartate (NMDA) antagonist with rapid and long-lasting antidepressant effects, but how the drug shows its sustained effects is still a matter of controversy. The objectives were to evaluate the mechanisms for KET rapid (30 min) and long-lasting (15 and 30 days after) antidepressant effects in mice. A single dose of KET (2, 5, or 10 mg/kg, po) was administered to male Swiss mice and the forced swim test (FST) was performed 30 min, 15, or 30 days later. Imipramine (IMI, 30 mg/kg, ip), a tricyclic antidepressant drug, was used as reference. The mice were euthanized, separated into two time-point groups (D1, first day after KET injection; D30, 30 days later), and brain sections were processed for glycogen synthase kinase-3 (GSK-3), histone deacetylase (HDAC), brain-derived neurotrophic factor (BDNF), and glial fibrillary acidic protein (GFAP) immunohistochemical assays. KET (5 and 10 mg/kg) presented rapid and long-lasting antidepressant-like effects. As expected, the immunoreactivities for brain GSK-3 and HDAC decreased compared to control groups in all areas (striatum, DG, CA1, CA3, and mainly pre-frontal cortex, PFC) after KET injection. Increases in BDNF immunostaining were demonstrated in the PFC, DG, CA1, and CA3 areas at D1 and D30 time-points. GFAP immunoreactivity was also increased in the PFC and striatum at both time-points. In conclusion, KET changed brain BDNF and GFAP expressions 30 days after a single administration. Although neuroplasticity could be involved in the observed effects of KET, more studies are needed to explain the mechanisms for the drug’s sustained antidepressant-like effects.
Highlights
Major depressive disorder (MDD) is a severe and debilitating psychiatric disease, for which the available antidepressant drugs do not always show a good response in a large percentage of the depressive population [1]
glycogen synthase kinase-3 (GSK-3) is shown to be an important target for KET rapid antidepressant effects, mediated by enhanced a-amino-3-hydroxy-5-methyl-4isoxazolepropionic acid (AMPA), resulting from the drug NMDA inhibition [5]
We showed that KET exhibits antinociceptive and anti-inflammatory effects [15] and, in addition, we observed that the monoaminergic pathways and inhibition of monoamine transporters are involved with the antidepressant-like effect of KET
Summary
Major depressive disorder (MDD) is a severe and debilitating psychiatric disease, for which the available antidepressant drugs do not always show a good response in a large percentage of the depressive population [1]. The inhibition of glycogen synthase kinase-3 (GSK-3 beta) modulates m-TOR signaling and may potentially augment the effects of antidepressants, such as KET, it is unclear whether GSK-3 directly mediates this drug effect. GSK-3 is shown to be an important target for KET rapid antidepressant effects, mediated by enhanced a-amino-3-hydroxy-5-methyl-4isoxazolepropionic acid (AMPA), resulting from the drug NMDA inhibition [5]. Several classes of serotonin-modulating drugs, such as antidepressants, regulate GSK-3 by inhibiting its brain activity. This inhibition reinforces the importance of GSK-3 as a potential therapeutic target in neuropsychiatric diseases associated with an abnormal serotonin function [6]
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