DOWN-REGULATION OF RAT-BRAIN 5-HT UPTAKE CARRIERS AFTER TREATMENT WITH HIGH-DOSES OF D-FENFLURAMINE

Male rats were treated with 10 mg/kg D-fenfluramine (DF) i.p., twice a day for 4 days. Five days later there was a strong reduction (70-100% ) in the B-max of [H-3]citalopram binding and the V-max of [H-3]5-HT u ptake in cortical and hippocampal synaptosomes; 2 months after the tre atment these parameters were reduced by 40-70%. The effect of treatmen t was also evaluated in synaptosomes preloaded with [H-3]5-HT, superfu sed and exposed for 3 min to a releasing stimulus (15 mM K+ or 0.5 mu M DF). In our experimental conditions, the stimulated [H-3]5-HT releas e is Ca2+-dependent and takes place only from 5-HT nerve endings. The K+-stimulated release was not consistently altered by the DF treatment whereas DF-stimulated [H-3]5-HT release was markedly reduced, either 5 days and 2 months after the treatment. The effect of chronic DF was different from the effect of i.c.v. 5,7-DHT, a specific 5-HT neurotoxi n which completely abolished the K+-induced release. Since the decreas e of synaptosomal [H-3]5-HT uptake induced by 5,7-DHT (82%) was simila r to that found after chronic DF (70-80%), these data suggest that the decrease of 5-HT uptake sites induced by chronic DF is not (only) due to neurodegeneration. That chronic DF could induce a functional down- regulation of 5-HT uptake sites (i.e. decreased density per intact ner ve ending) was suggested by the decrease of DF-induced release, since the releasing activity of DF is dependent on functional 5-HT uptake si tes. However, due to the characteristics of our model, our results are compatible with either the absence or the presence of a concomitant, partial neurodegeneration of 5-HT nerve endings in DF-treated rats. In summary, our data indicate that after treatment with high doses of DF , the 5-HT uptake carriers undergo a long-lasting down-regulation, thu s totally or partly explaining the lower [H-3]citalopram binding and t he lower synaptosomal [H-3]5-HT uptake.