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 journalArticle

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

Fingerprint

Fenfluramine
Serotonin
Down-Regulation
Brain
Nerve Endings
Citalopram
Synaptosomes
Neurotoxins

Keywords

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

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Down-regulation of rat brain 5-HT uptake carriers after treatment with high doses of D-fenfluramine. / Gobbi, Marco; Mancini, Laura; Presti, Maria Laura; Mennini, Tiziana.

In: Brain Research, Vol. 730, No. 1-2, 19.08.1996, p. 165-172.

Research output: Contribution to journalArticle

Gobbi, Marco ; Mancini, Laura ; Presti, Maria Laura ; Mennini, Tiziana. / Down-regulation of rat brain 5-HT uptake carriers after treatment with high doses of D-fenfluramine. In: Brain Research. 1996 ; Vol. 730, No. 1-2. pp. 165-172.
@article{a7bfc6a6639a437187c5836d4e6e1a5f,
title = "Down-regulation of rat brain 5-HT uptake carriers after treatment with high doses of D-fenfluramine",
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.",
keywords = "D-fenfluramine, neurotoxicity, rat brain, serotonin release, serotonin uptake carrier, synaptosome",
author = "Marco Gobbi and Laura Mancini and Presti, {Maria Laura} and Tiziana Mennini",
year = "1996",
month = "8",
day = "19",
doi = "10.1016/S0006-8993(96)00435-0",
language = "English",
volume = "730",
pages = "165--172",
journal = "Brain Research",
issn = "0006-8993",
publisher = "Elsevier",
number = "1-2",

}

TY - JOUR

T1 - Down-regulation of rat brain 5-HT uptake carriers after treatment with high doses of D-fenfluramine

AU - Gobbi, Marco

AU - Mancini, Laura

AU - Presti, Maria Laura

AU - Mennini, Tiziana

PY - 1996/8/19

Y1 - 1996/8/19

N2 - 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.

AB - 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.

KW - D-fenfluramine

KW - neurotoxicity

KW - rat brain

KW - serotonin release

KW - serotonin uptake carrier

KW - synaptosome

UR - http://www.scopus.com/inward/record.url?scp=0030593704&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0030593704&partnerID=8YFLogxK

U2 - 10.1016/S0006-8993(96)00435-0

DO - 10.1016/S0006-8993(96)00435-0

M3 - Article

C2 - 8883900

AN - SCOPUS:0030593704

VL - 730

SP - 165

EP - 172

JO - Brain Research

JF - Brain Research

SN - 0006-8993

IS - 1-2

ER -