Subchronic fluoxetine treatment induces a transient potentiation of amphetamine-induced hyperlocomotion: possible pharmacokinetic interaction

The results of the present study show that 5 days of systemic treatment wit h fluoxetine (5 mg/kg) resulted in an augmented locomotor response to amphe tamine (0.5 mg/kg). This augmented response to amphetamine was observed 24 and 48 h, but not 5 days, after the cessation of fluoxetine treatment. Subc hronic fluoxetine treatment also produced an increase in the brain concentr ation of amphetamine when rats were challenged with amphetamine 48 h, but n ot 5 days, after the cessation of fluoxetine treatment. Thus, the effect of subchronic fluoxetine in augmenting amphetamine-induced hyperactivity was consistent with the effect of subchronic fluoxetine in augmenting the amphe tamine concentration in the brain. This pattern of results indicates that s ubchronic fluoxetine potentiates the response to amphetamine within a limit ed time-window, and that this potentiating effect is likely to be due to th e reduced metabolism of amphetamine via the inhibition of cytochrome P450 b y fluoxetine and/or its metabolite norfluoxetine. (C) 2000 Lippincott Willi ams & Wilkins.