Ketamine decreases HPA axis reactivity to a novel stressor in male but not female mice

Ketamine is an antidepressant drug that interacts with the hypothalamic-pituitary-adrenal (HPA) axis, but whether this interaction is important for its behavioral effect is unknown. The goal of this experiment was to determine whether the behavioral response to ketamine depends on intact HPA axis function. Male and female C57BL/6J mice underwent chronic unpredictable stress prior to ketamine (30 mg/kg, i.p.) or vehicle treatment, with or without the glucocorticoid synthesis inhibitor metyrapone (20 mg/kg, i.p.) to block adrenal corticosterone production. Mice were tested in the forced swim test (FST) and open field test one and two days after injection, respectively. Fecal corticosterone was measured at select time points. No significant drug effects on behavior were observed. Males consistently had higher fecal corticosterone levels and stress-induced increases than females. Ketamine lowered the fecal corticosterone response to the FST only in males. These data show that ketamine after chronic stress decreases the corticosterone response to a novel stressor (the FST) in males, but not females. Corticosterone levels in all mice correlated with immobility in the FST, suggesting that shared neural circuitry could mediate both endocrine and behavioral responses. This circuitry may be ketamine-responsive only in males.