Abstract
Ketamine is a N-methyl-D-aspartate receptor (NMDAR) antagonist that produces rapid antidepressant responses in individuals with major depressive disorder. The antidepressant action of ketamine has been linked to blocking NMDAR activation at rest, which inhibits eukaryotic elongation factor 2 kinase leading to desuppression of protein synthesis and synaptic potentiation in the CA1 region of the hippocampus. Here, we investigated ketamine mediated antidepressant response and the resulting synaptic potentiation in juvenile animals. We found that ketamine did not produce an antidepressant response in juvenile animals in the novelty suppressed feeding or the forced swim test. In addition ketamine application failed to trigger synaptic potentiation in hippocampal slices obtained from juvenile animals, unlike its action in slices from adult animals. The inability of ketamine to trigger an antidepressant response or subsequent synaptic plasticity processes suggests a developmental component to ketamine mediated antidepressant efficacy. We also show that the NMDAR antagonist AP5 triggers synaptic potentiation in mature hippocampus similar to the action of ketamine, demonstrating that global competitive blockade of NMDARs is sufficient to trigger this effect. These findings suggest that global blockade of NMDARs in developmentally mature hippocampal synapses are required for the antidepressant efficacy of ketamine.
Highlights
Major depressive disorder (MDD) is a serious mental condition in which there is a need for fast acting treatment
KETAMINE DOES NOT TRIGGER A RAPID ANTIDEPRESSANT RESPONSE IN JUVENILE ANIMALS We investigated whether ketamine triggers an antidepressant response in 4 week old C57BL/6 juvenile mice
We found no difference between the ketamine and vehicle treated mice in the latency to consume the food pellet in the juvenile mice suggesting that ketamine did not trigger an antidepressant response (Figure 1A)
Summary
Major depressive disorder (MDD) is a serious mental condition in which there is a need for fast acting treatment. The behavioral as well as the synaptic effects of ketamine are dependent on the function of eukaryotic elongation factor 2 (eEF2) kinase and protein synthesis as ketamine failed to elicit a behavioral response or potentiation on the eEF2 kinase null mice as well as after application of protein translation blocker anisomycin (Autry et al, 2011; Nosyreva et al, 2013) These studies have provided a strong correlation between the synaptic action of ketamine and its rapid antidepressant effects, they have not yet addressed whether this effect is dependent on the stage of synapse development. These earlier studies have not addressed whether the synaptic effect of ketamine and another use-dependent NMDAR blocker MK-801 could be mimicked by the widely used competitive non-use dependent NMDAR antagonist D-AP5 [D-AP5 (2R)-amino-5-phosphonopentanoate]
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