GBR 13098, a selective dopamine uptake inhibitor; behavioural, biochemical and electrophysiological studies.

Previous in vitro studies have suggested that GBR 13098 (1-(2-(bis(4-fluophenyl methoxy) ethyl)-4-(3-(4-fluorophenyl)-propyl)piperazine) dimethane sulfonate) acts as a selective dopamine uptake inhibitor. In the present study, behavioural, biochemical and electrophysiological effects of GBR 13098 in rats were analyzed. GBR 13098 (10-40 mg/kg, i.p.) increased locomotor activity of habituated rats. The effect was almost totally prevented by pretreatment with the monoamine-depleting drug reserpine (5 mg/kg, 6 h) or the dopamine receptor antagonist haloperidol (0.3 mg/kg, 30 min). GBR 13098 (20 mg/kg, i.p.) reduced DOPA formation in the striatum and in the limbic region, whereas the dopamine poor hemispheres were unaffected in this regard. GBR 13098 (0.1-20 mg/kg, i.v.; or 20 mg/kg, i.p.) did not alter the spontaneous firing rate of dopamine neurons in the substantia nigra zona compacta. However, pretreatment with the drug (20 mg/kg, i.p., 10-30 min) enhanced the inhibitory response of microiontophoretically applied dopamine onto the dopamine neurons of substantia nigra. Taken together, the present series of experiments show that GBR 13098 acts as a specific and potent inhibitor of dopamine uptake in brain. Present electrophysiological data are in line with the existence of a somatic or dendritic uptake system of dopamine within the substantia nigra but do not support the notion that the impulse activity of nigral dopamine neurons is regulated via a striatonigral feedback pathway.