Down-regulation of rat brain 5-HT uptake carriers after treatment with high doses of D-fenfluramine

Marco Gobbi, Laura Mancini, Maria Laura Presti, Tiziana Mennini

Research output: Contribution to journalArticlepeer-review

Abstract

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 [3H]citalopram binding and the V(max) of [3H]5-HT uptake in cortical and hippocampal synaptosomes; 2 months after the treatment these parameters were reduced by 40-70%. The effect of treatment was also evaluated in synaptosomes preloaded with [3H]5-HT, superfused and exposed for 3 min to a releasing stimulus (15 mM K+ or 0.5 μM DF). In our experimental conditions, the stimulated [3H]5-HT release 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 [3H]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 neurotoxin which completely abolished the K+-induced release. Since the decrease of synaptosomal [3H]5-HT uptake induced by 5,7-DHT (82%) was similar 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 nerve ending) was suggested by the decrease of DF-induced release, since the releasing activity of DF is dependent on functional 5-HT uptake sites. 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, thus totally or partly explaining the lower [3H]citalopram binding and the lower synaptosomal [3H]5-HT uptake.

Original languageEnglish
Pages (from-to)165-172
Number of pages8
JournalBrain Research
Volume730
Issue number1-2
DOIs
Publication statusPublished - Aug 19 1996

Keywords

  • D-fenfluramine
  • neurotoxicity
  • rat brain
  • serotonin release
  • serotonin uptake carrier
  • synaptosome

ASJC Scopus subject areas

  • Neuroscience(all)

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