Loss of the sustained antidepressant-like effect of (2R,6R)-hydroxynorketamine in NMDA receptor GluN2D subunit knockout mice.

Ketamine, an N-methyl-d-aspartate (NMDA) receptor antagonist, has attracted attention for its acute and sustained antidepressant effects in patients with depression. Hydroxynorketamine (HNK), a metabolite of ketamine, exerts antidepressant effects without exerting ketamine's side effects and has attracted much attention in recent years. However, the detailed pharmacological mechanism of action of HNK remains unclear. We previously showed that the GluN2D NMDA receptor subunit is important for sustained antidepressant-like effects of (R)-ketamine. Therefore, we investigated whether the GluN2D subunit is involved in antidepressant-like effects of (2R,6R)-HNK and (2S,6S)-HNK. Treatment with (2R,6R)-HNK but not (2S,6S)-HNK exerted acute and sustained antidepressant-like effects in the tail-suspension test in wildtype mice. Interestingly, sustained antidepressant-like effects of (2R,6R)-HNK were abolished in GluN2D-knockout mice, whereas acute antidepressant-like effects were maintained in GluN2D-knockout mice. When expression levels of GluN2A and GluN2B subunits were evaluated, a decrease in GluN2B protein expression in the nucleus accumbens was found in stressed wildtype mice but not in stressed GluN2D-knockout mice. These results suggest that the GluN2D subunit and possibly the GluN2B subunit are involved in the sustained antidepressant-like effect of (2R,6R)-HNK.

Keratinocyte-Derived Cytokine in the Hippocampus Disrupts Extinction of Conditioned Fear Memory in Tumor-Bearing Mice.

While patients with cancer show a higher prevalence of psychiatric disorders than the general population, the mechanism underlying this interaction remains unclear. The present study examined whether tumor-bearing (TB) mice show psychological changes using the conditioned fear paradigm and the role of cytokines in these changes. TB mice were established by transplantation with mouse osteosarcoma AXT cells. These TB mice were then found to exhibit disruption in extinction of conditioned fear memory. Eighteen cytokines in serum were increased in TB mice, among which i.c.v. injection of interleukin (IL)-1ß and IL-6 strengthened fear memory in normal mice. Contents of IL-17 and keratinocyte-derived cytokine (KC) in the amygdala and KC in the hippocampus were increased in TB mice. KC mRNA in both the amygdala and hippocampus was also increased in TB mice, and i.c.v. injection of KC dose-dependently strengthened fear memory in normal mice. In addition, injection of IL-1ß, but not IL-6, increased KC mRNA in the amygdala and hippocampus. In TB mice KC mRNA was increased in both astrocytes and microglia of the amygdala and hippocampus. The microglia inhibitor minocycline, but not the astrocyte inhibitor fluorocitrate, alleviated disruption in extinction of conditioned fear memory in TB mice. Microinjection of KC into the hippocampus, but not into the amygdala, increased fear memory in normal mice. These findings indicate that TB mice show an increase in serum cytokines, including IL-1ß, that increases KC production in microglia of the hippocampus, which then disrupts extinction of fear memory.