Behavioural and neurochemical evidence that the antimicrobial agent oxolinic acid is a dopamine uptake inhibitor

The antimicrobial agent oxolinic acid, injected i.p. in mice, induced a dos e dependent increase in locomotor activity. This stimulation culminated at the 32 mg/kg dose and became smaller for higher doses (64-128 mg/kg). When opposed to increasing doses (50-100-200 mu g/kg i.p.) of haloperidol (D2 do pamine receptor antagonist), the stimulant locomotor effect of 32 mg/kg oxo linic acid was not significantly reversed. On the contrary increasing doses (7.5-15-30 mu g/kg s.c.) of SCH 23390 (D1 dopamine receptor antagonist) in hibited the stimulant locomotor effect. In mice made completely akinetic by a pretreatment with reserpine (4 mg/kg s.c., 18 h before testing), dexamph etamine (2 mg/kg s.c.) reversed this akinesia and even displayed a stimulan t activity, similar to that observed in mice not treated by reserpine. On t he contrary, oxolinic acid (32 mg/kg) did not reverse the reserpine induced akinesia and even opposed the reversion induced by dexamphetamine. In a sy naptosomal fraction prepared from striatum of rats, oxolinic acid inhibited the H-3 dopamine uptake with an IC50 =4.3+/-0.6x10(-6) M. Finally, in mice injected i.v. with a tracer dose of H-3 WIN 35428 (1 mu Ci) (a dopamine up take blocker), 32 mg/kg oxolinic acid, i.p. administered, reduced by about 50% the specific binding of the radioligand to striatal dopamine carriers. It is concluded that the stimulant locomotor effect of oxolinic acid depend s on the blockade of the neuronal dopamine uptake complex. (C) 1998 Elsevie r Science B.V./ECNP. All rights reserved.