Recent studies have demonstrated that an acute, low dose of ketamine, a non-competitive NMDA receptor antagonist, provides rapid and sustained antidepressant effects in patients with major depressive disorder. Studies in rodents have shown that the antidepressant properties of ketamine are due to an increase in dendritic spine density in the cortex. Our goal was to determine whether these effects are specific to ketamine and whether they are dependent on dose, drug regimen and brain region. We observed that the effects of ketamine on spine density were dependent on dose and drug regimen and were also brain region specific. In addition, MK-801, another NMDA receptor antagonist, did not demonstrate the same effects on spine density as ketamine. Furthermore, genetic NMDA receptor hypofunction significantly reduced spine density. Our studies demonstrate that while acute ketamine treatment leads to an increase in cortical spine density, chronic administration has opposite and potentially detrimental effects.

Recent studies have demonstrated that an acute, low dose of ketamine, a non-competitive NMDA receptor antagonist, provides rapid and sustained antidepressant effects in patients with major depressive disorder. Studies in rodents have shown that the antidepressant properties of ketamine are due to an increase in dendritic spine density in the cortex. Our goal was to determine whether these effects are specific to ketamine and whether they are dependent on dose, drug regimen and brain region. We observed that the effects of ketamine on spine density were dependent on dose and drug regimen and were also brain region specific. In addition, MK-801, another NMDA receptor antagonist, did not demonstrate the same effects on spine density as ketamine. Furthermore, genetic NMDA receptor hypofunction significantly reduced spine density. Our studies demonstrate that while acute ketamine treatment leads to an increase in cortical spine density, chronic administration has opposite and potentially detrimental effects.