The corticosteroid synthesis inhibitor metyrapone markedly enhances the behavioural effects of d-amphetamine

The clinically utilized corticosteroid synthesis inhibitor metyrapone attenuates the behavioural effects of cocaine in the rat. Given the potential therapeutic implications of this interaction, we felt it important to determine if metyrapone's action would generalize to another widely abused psychostimulant, namely d-amphetamine. However, rather than producing attenuation, metyrapone preadministration (3 x 100 mg/kg) markedly enhanced both the locomotor activating and stereotypy-inducing actions of d-amphetamine (dose equivalent to 2.5 mg/kg free base). The fact that the corticosteroid synthesis inhibitor trilostane did not affect the behavioural action of d-amphetamine suggests that inhibition of corticoid synthesis does not underlie the action of metyrapone. Instead, it is argued that inhibition of debrisoquine hydroxylase (cytochrome p450 2D1), an enzyme involved in the metabolism of d-amphetamine, represents the critical mechanism of action.