The potentiating effect of sertraline and fluoxetine on amphetamine-induced locomotor activity is not mediated by serotonin.

Sertraline dose-dependently increased the locomotor stimulating effect of amphetamine. At the highest dose, 20 mg/kg sertraline had a biphasic effect on amphetamine-induced hyperactivity, producing an initial reduction in amphetamine-induced hyperactivity that was later followed by an augmentation of amphetamine-induced hyperactivity in the last hour of the 3-h test. Sertraline, at doses of 5 and 10 mg/kg, produced an augmentation of amphetamine-induced hyperactivity over the last 2 h of the 3-h test session. Further, there was an increase in the concentration of amphetamine in the brain in rats pretreated with 5 mg/kg sertraline. Both sertraline (5 mg/kg) and fluoxetine (5 mg/kg) produced an augmentation of amphetamine-induced hyperactivity that was unaltered by a serotonergic lesion of the median and dorsal raphe nuclei that resulted in a greater than 90% depletion of serotonin in hippocampus, striatum, and nucleus accumbens. Further, both sertraline and fluoxetine inhibited spontaneous locomotor activity and this effect was also unaltered by the depletion of serotonin. Thus, serotonergic neurotransmission is not essential for the effects of sertraline and fluoxetine on spontaneous and amphetamine-induced locomotion. It is probable that sertraline and fluoxetine augment the locomotor stimulatory effect of amphetamine by decreasing the metabolism of amphetamine, perhaps via actions on cytochrome P450 isozymes.