Metyrapone displays antidepressant-like properties in preclinical paradigms

A possible involvement of glucocorticoids in the aetiology of depression is suggested by commonly reported hypothalamo-pituitary-adrenocortical (HPA) axis abnormalities in depressed patients, the modulation of the HPA axis by antidepressant drugs and clinical reports of antidepressant efficacy with antiglucocorticoid agents. The effects of treatment with metyrapone, a gluc ocorticoid synthesis inhibitor, and the tricyclic antidepressant, desiprami ne, in two rodent models of depression, namely the forced swim test and olf actory bulbectomized (OB) rat, were investigated. In addition, the effect o f chronic metyrapone and desipramine treatments on the hypothermic response to a challenge with the 5-HT1A agonist, 8-hydroxy-2-(di-n-propylamino) tet ralin (8-OH-DPAT) was assessed. There is experimental evidence to suggest t hat attenuation of the hypothermic response to this agonist occurs followin g chronic antidepressant treatment. In the forced swim test, metyrapone (50 mg/kg) and desipramine (10 mg/kg) significantly reduced the immobility tim e. In the olfactory bulbectomized rat model of depression, chronic administ ration (14 days) of metyrapone (50 mg/kg b.i.d.) and desipramine (5 mg/kg b .i.d.) attenuated the OB-related hyperactivity in a novel stressful environ ment. Chronic metyrapone treatment (50 mg/kg b.i.d.) attenuated the hypothe rmic response to an acute challenge with 8-OH-DPAT (0.05 mg/kg SC), indicat ing a change to the sensitivity of 5-HT1A receptors. These preclinical test s demonstrate an antidepressant-like profile for metyrapone. Further explor ation of the therapeutic potential and possible mechanism of action of gluc ocorticoid antagonism in depression is warranted.