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

The clinically utilized corticosteroid synthesis inhibitor metyrapone atten uates the behavioural effects of cocaine in the rat. Given the potential th erapeutic implications of this interaction, we felt it important to determi ne if metyrapone's action would generalize to another widely abused psychos timulant, namely d-amphetamine. However, rather than producing attenuation, metyrapone preadministration (3 X 100 mg/kg) markedly enhanced both the lo comotor activating and stereotypy-inducing actions of d-amphetamine (dose e quivalent to 2.5 mg/kg free base). The fact that the corticosteroid synthes is inhibitor trilostane did not affect the behavioural action of d-amphetam ine suggests that inhibition of corticoid synthesis does not underlie the a ction 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.