Antidepressant-like effects of low ketamine dose is associated with increased hippocampal AMPA/NMDA receptor density ratio in female Wistar–Kyoto rats

Abstract

Preclinical as well as limited clinical studies indicate that ketamine, a non-competitive glutamate NMDA receptor antagonist, may exert a quick and prolonged antidepressant effect. It has been postulated that ketamine action is due to inhibition of NMDA and stimulation of AMPA receptors. Here, we sought to determine whether ketamine would exert antidepressant effects in Wistar-Kyoto (WKY) rats, a putative animal model of depression and whether this effect would be associated with changes in AMPA/NMDA receptor densities in the hippocampus. Adult female WKY rats and their control Wistar rats were subjected to acute and chronic ketamine doses and their locomotor activity (LMA) and immobility in the forced swim test (FST) were evaluated. Hippocampal AMPA and NMDA receptor densities were also measured following a chronic ketamine dose. Ketamine, both acutely (0.5–5.0 mg/kg ip) and chronically (0.5–2.5 mg/kg daily for 10 days) resulted in a dose-dependent and prolonged decrease in immobility in the FST in WKY rats only, suggesting an antidepressant-like effect in this model. Chronic treatment with an effective dose of ketamine also resulted in an increase in AMPA/NMDA receptor density ratio in the hippocampus of WKY rats. LMA was not affected by any ketamine treatment in either strain. These results indicate a rapid and lasting antidepressant-like effect of a low ketamine dose in WKY rat model of depression. Moreover, the increase in AMPA/NMDA receptor density in hippocampus could be a contributory factor to behavioral effects of ketamine. These findings suggest potential therapeutic benefit in simultaneous reduction of central NMDA and elevation of AMPA receptor function in treatment of depression.

Observation of Distressed Conspecific as a Model of Emotional Trauma Generates Silent Synapses in the Prefrontal-Amygdala Pathway and Enhances Fear Learning, but Ketamine Abolishes those Effects

“…Normalization of AMPAR/NMDAR ratio and elimination of silent synapses by ketamine are consistent with findings that ketamine increases AMPAR/NMDAR ratio and enhances Emotional trauma generates silent synapses W Ito et al surface expression of AMPAR (Maeng et al, 2008;Nosyreva et al, 2013;Tizabi et al, 2012). However, we did not detect increases in AMPAR/NMDAR in control mice injected with ketamine.…”

“…The reason for the discrepancy could be the timing of our measures. The reported increases were detected within minutes after single ketamine injection (Maeng et al, 2008;Nosyreva et al, 2013) or after 10 days of repeated injections (Tizabi et al, 2012), whereas our recordings were done 24 h after injection. While the network process leading to the formation of silent synapses after OF remains to be determined, a desynchronized neuronal activity has been shown to increase the number of AMPAR-silent synapses (Huupponen et al, 2013).…”

“…Evidence that ketamine increases AMPAR over NMDAR function (Maeng et al, 2008;Nosyreva et al, 2013;Tizabi et al, 2012) predicts that ketamine counters the effects from OF. Mice were injected with ketamine (10 mg/kg) or saline immediately after OF, followed by the PA training on the next day.…”

Withdrawal from Acute Amphetamine Induces an Amygdala-Driven Attenuation of Dopamine Neuron Activity: Reversal by Ketamine

“…In animal models of depression, ketamine has been shown to reverse despair behavior and anhedonia, supposedly via an effect on the hippocampus. Indeed, ketamine rapidly increases mTOR-dependent synaptogenesis in the hippocampus (Garcia et al, 2008) and increases hippocampal brainderived neurotrophic factor (BDNF) and mammalian target of rapamycin levels during the FST in rats (Tizabi et al, 2012). …”

Dietary magnesium deficiency alters gut microbiota and leads to depressive-like behaviour

“…Interestingly, blocking the NMDAr by antagonists has shown increased NMDAr/α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor density in hippocampus and to simulate antidepressant effect (41) as well as the co-administration of Mg (34,43). Mg depletion may also play a role in the monoaminergic systems as Mg is a cofactor in activating tryptophan, a precursor in dopamine and serotonin synthesis (26,44).…”