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High-dose fenfluramine administration decreases serotonin transporter binding, but not serotonin transporter protein levels, in rat forebrain.
Synapse 2003; 50(3):233-9S

Abstract

Administration of D-fenfluramine (D-FEN) or parachloroamphetamine (PCA) can produce long-lasting decreases in serotonin transporter (SERT) binding and tissue levels of serotonin (5-HT) in rat forebrain. These changes have been viewed as evidence for 5-HT neurotoxicity, but no studies have measured SERT protein levels. In the present study, we determined the effect of high-dose D-FEN or PCA, administered according to a "neurotoxic" dosing regimen, on the density of SERT sites using ligand binding methods and on SERT protein levels using Western blots. Rats were sacrificed 2 days and 2 weeks after administration of drug or saline. The density of SERT was determined in homogenates of caudate and whole brain minus caudate. D-FEN and PCA decreased SERT binding by 30-60% in both tissues and at both time points. Similarly, D-FEN and PCA administration profoundly decreased tissue 5-HT and 5-HIAA in frontal cortex. Despite the large decreases in SERT binding and depletion of tissue 5-HT that occurred with D-FEN administration, SERT protein expression, as determined by Western blot analysis, did not change in either tissue or time point. PCA administration decreased SERT protein by about 20% only at the 2-day point in the caudate. Drug treatments did not change expression of glial fibrillary acidic protein (GFAP), a hallmark indicator of neuronal damage, in whole brain minus caudate in the 2-week group. These results support the hypothesis that decreases in tissue 5-HT and SERT binding sites induced by D-FEN and PCA reflect neuroadaptive changes, rather than neurotoxic effects.

Authors+Show Affiliations

Clinical Psychopharmacology Section, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland 21224, USA. rrothman@intra.nida.nih.govNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

14515341

Citation

Rothman, Richard B., et al. "High-dose Fenfluramine Administration Decreases Serotonin Transporter Binding, but Not Serotonin Transporter Protein Levels, in Rat Forebrain." Synapse (New York, N.Y.), vol. 50, no. 3, 2003, pp. 233-9.
Rothman RB, Jayanthi S, Wang X, et al. High-dose fenfluramine administration decreases serotonin transporter binding, but not serotonin transporter protein levels, in rat forebrain. Synapse. 2003;50(3):233-9.
Rothman, R. B., Jayanthi, S., Wang, X., Dersch, C. M., Cadet, J. L., Prisinzano, T., ... Baumann, M. H. (2003). High-dose fenfluramine administration decreases serotonin transporter binding, but not serotonin transporter protein levels, in rat forebrain. Synapse (New York, N.Y.), 50(3), pp. 233-9.
Rothman RB, et al. High-dose Fenfluramine Administration Decreases Serotonin Transporter Binding, but Not Serotonin Transporter Protein Levels, in Rat Forebrain. Synapse. 2003 Dec 1;50(3):233-9. PubMed PMID: 14515341.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - High-dose fenfluramine administration decreases serotonin transporter binding, but not serotonin transporter protein levels, in rat forebrain. AU - Rothman,Richard B, AU - Jayanthi,Subramaniam, AU - Wang,Xiaoying, AU - Dersch,Christina M, AU - Cadet,Jean L, AU - Prisinzano,Thomas, AU - Rice,Kenner C, AU - Baumann,Michael H, PY - 2003/9/30/pubmed PY - 2004/1/7/medline PY - 2003/9/30/entrez SP - 233 EP - 9 JF - Synapse (New York, N.Y.) JO - Synapse VL - 50 IS - 3 N2 - Administration of D-fenfluramine (D-FEN) or parachloroamphetamine (PCA) can produce long-lasting decreases in serotonin transporter (SERT) binding and tissue levels of serotonin (5-HT) in rat forebrain. These changes have been viewed as evidence for 5-HT neurotoxicity, but no studies have measured SERT protein levels. In the present study, we determined the effect of high-dose D-FEN or PCA, administered according to a "neurotoxic" dosing regimen, on the density of SERT sites using ligand binding methods and on SERT protein levels using Western blots. Rats were sacrificed 2 days and 2 weeks after administration of drug or saline. The density of SERT was determined in homogenates of caudate and whole brain minus caudate. D-FEN and PCA decreased SERT binding by 30-60% in both tissues and at both time points. Similarly, D-FEN and PCA administration profoundly decreased tissue 5-HT and 5-HIAA in frontal cortex. Despite the large decreases in SERT binding and depletion of tissue 5-HT that occurred with D-FEN administration, SERT protein expression, as determined by Western blot analysis, did not change in either tissue or time point. PCA administration decreased SERT protein by about 20% only at the 2-day point in the caudate. Drug treatments did not change expression of glial fibrillary acidic protein (GFAP), a hallmark indicator of neuronal damage, in whole brain minus caudate in the 2-week group. These results support the hypothesis that decreases in tissue 5-HT and SERT binding sites induced by D-FEN and PCA reflect neuroadaptive changes, rather than neurotoxic effects. SN - 0887-4476 UR - https://www.unboundmedicine.com/medline/citation/14515341/High_dose_fenfluramine_administration_decreases_serotonin_transporter_binding_but_not_serotonin_transporter_protein_levels_in_rat_forebrain_ L2 - https://doi.org/10.1002/syn.10266 DB - PRIME DP - Unbound Medicine ER -