Chronic adrenocorticotrophic hormone treatment alters tricyclic antidepressant efficacy and prefrontal monoamine tissue levels

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Abstract

HIGHLIGHTS

★ ACTH pre-treatment blocked antidepressant effect of imipramine in forced swim test. ★ PFC serotonin, noradrenaline and adrenaline were increased in ACTH-treated animals. ★ PFC dopamine was markedly decreased in ACTH pre-treated animals. ★ Glucocorticoid responses were downregulated by ACTH treatment.

Several animal models are currently utilised in the investigation of major depressive disorder; however, each is validated by its response to antidepressant pharmacotherapy. Few animal models consider the notion of antidepressant treatment resistance. Chronic daily administration of adrenocorticotropic hormone (ACTH) or corticosterone can alter behavioural responses to antidepressants, effectively blocking antidepressant efficacy. Herein, we demonstrate that ACTH-(1-24) (100 μg/day; 14 days) blocks the immobility-reducing ‘antidepressant’ effects of a single dose of imipramine (10 mg/kg) in the forced swim test. This finding was accompanied by altered monoamine tissue levels in the prefrontal cortex (PFC) 1 h after exposure to the acute stress of the forced swim test. PFC tissue from ACTH pre-treated animals contained significantly higher serotonin, noradrenaline and adrenaline concentrations relative to saline pre-treated controls. Conversely, dopamine levels were significantly decreased. Altered plasma corticosterone responses to ACTH injections were observed over the treatment course. Measures were taken on treatment days 1, 4, 8, 11, 14 and 15. ACTH administration initially enhanced plasma corticosterone levels, however, these normalised to levels consistent with control animals by day 14. No differences in corticosterone levels were observed across the treatment time course in saline-treated animals. Taken together these results indicate that pre-treatment with ACTH (100 μg/day; 14 days) blocks the antidepressant effects of imipramine (10 mg/kg), significantly alters key PFC monoamine responses to stress and downregulates glucocorticoid responses. These results suggest that chronic ACTH treatment is a promising paradigm for elucidation of mechanisms mediating antidepressant treatment resistance.

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