Ketamine metabolism via hepatic CYP450 isoforms contributes to its sustained antidepressant actions.

(R,S)-ketamine (ketamine) has rapid and sustained antidepressant (AD) efficacy at sub-anesthetic doses in depressed patients. A metabolite of ketamine, including (2R,6R)-hydroxynorketamine ((6)-HNKs) has been reported to exert antidepressant actions in rodent model of anxiety/depression. To further understand the specific role of ketamine's metabolism in the AD actions of the drug, we evaluated the effects of inhibiting hepatic cytochrome P450 enzymes on AD responses.

[Ketamine: a neuropsychotropic drug with an innovative mechanism of action].

Ketamine, a non-competitive antagonist of the N-methyl-D-aspartate-glutamate receptor (R-NMDA), has a rapid (from 24 h post-dose) and prolonged (up to one week) antidepressant effect in treatment resistant depression and in rodent models of anxiety/depression. Arguments regarding its cellular and molecular mechanisms underlying its antidepressant activity mainly come from animal studies. However, debates still persist on the structural remodeling of frontocortical/hippocampal neurons and the role of excitatory/inhibitory neurotransmitters involved in its behavioral effect.

A tale of two receptors: simultaneous targeting of NMDARs and 5-HT Rs exerts additive effects against stress.

Background: Serotonin (5-HT) receptors and -methyl-D-aspartate receptors (NMDARs) have both been implicated in the pathophysiology of depression and anxiety disorders. Here, we evaluated whether targeting both receptors through combined dosing of ( , )-ketamine, an NMDAR antagonist, and prucalopride, a serotonin type IV receptor (5-HT R) agonist, would have additive effects, resulting in reductions in stress-induced fear, behavioral despair, and hyponeophagia.

Methods: A single injection of saline (Sal), ( , )-ketamine (K), prucalopride (P), or a combined dose of ( , )-ketamine and prucalopride (K+P) was administered before or after contextual fear conditioning (CFC) stress in both sexes.

A complex relation between levels of adult hippocampal neurogenesis and expression of the immature neuron marker doublecortin.

We investigated the mechanisms underlying the effects of the antidepressant fluoxetine on behavior and adult hippocampal neurogenesis (AHN). After confirming our earlier report that the signaling molecule β-arrestin-2 (β-Arr2) is required for the antidepressant-like effects of fluoxetine, we found that the effects of fluoxetine on proliferation of neural progenitors and survival of adult-born granule cells are absent in the β-Arr2 knockout (KO) mice. To our surprise, fluoxetine induced a dramatic upregulation of the number of doublecortin (DCX)-expressing cells in the β-Arr2 KO mice, indicating that this marker can be increased even though AHN is not.