Dose-dependent suppression of adrenocortical activity with metyrapone: effects on emotion and memory

Different levels of circulating corticosterone are considered to produce different emotional states and effects on learning and memory. The purpose of the present study was to use different doses of the 11-beta-hydroxylase inhibitor metyrapone to produce dose-dependent inhibition of the synthesis of corticosterone and examine the consequences of that on several cognitive and emotional parameters. Systemic (SC) injections of metyrapone (25 or 50 mg/kg) dose-dependently suppressed increases in plasma concentrations of corticosterone induced by spatial training in a water maze, but did not affect plasma corticosterone levels in non-stressed rats. Treatment with the higher and lower dose of metyrapone also differentially affected behavioral measures of emotion and memory. Administration of 50 mg/kg, but not 25 mg/kg, of metyrapone impaired acquisition performance in the spatial water maze task. Both doses of metyrapone impaired retention. The impairment in retention was attenuated by dexamethasone (0.3 mg/kg) given systemically immediately after training, but not by corticosterone (0.3 mg/kg). During the exposure to a conditioned stressor of inescapable footshock, the higher, but not the lower dose of metyrapone attenuated fear-induced immobility. In contrast, the lower, but not the higher dose attenuated the anxiety state in an elevated plus-maze in a novel environment immediately after exposure to the conditioned stressor. It is suggested that emotion, learning, and memory are differentially affected by the different doses of metyrapone due to interference with different types of adrenal steroid receptors and consequent induction of various corticosterone receptor states.