In a mouse model of depression created by spared nerve injury, esketamine improved depression-like behaviors, such as increasing time spent in open arms and central area of an open field test and total distance traveled, while also increasing immobility in forced swimming and tail suspension tests. It raised the density of total and mature dendritic spines in the prefrontal cortex and increased expression of CRMP2 and PSD-95 proteins. These findings suggest esketamine promotes brain plasticity in the prefrontal cortex, possibly through changes in these proteins.
A single oral dose of ketamine (5 or 10 mg/kg) produced rapid (30 minutes) and long-lasting (up to 30 days) antidepressant-like effects in male Swiss mice, measured by the forced swim test. The tricyclic antidepressant imipramine served as a reference. Ketamine reduced immunoreactivity for GSK-3 and HDAC in several brain regions, especially the prefrontal cortex, and increased BDNF immunostaining in the prefrontal cortex, dentate gyrus, CA1, and CA3 areas at both 1 and 30 days after injection. GFAP immunoreactivity also increased in the prefrontal cortex and striatum at both time points. The authors conclude that ketamine alters brain BDNF and GFAP expression for 30 days after a single dose, but further studies are needed to explain the mechanisms of its sustained effects.