Research article summary (published 29 Nov 2003):

High-dose fenfluramine administration decreases serotonin transporter binding, but not serotonin transporter protein levels, in rat forebrain.

Full 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.

Author information

Author/s: Rothman, Richard B (RB); Jayanthi, Subramaniam (S); Wang, Xiaoying (X); Dersch, Christina M (CM); Cadet, Jean L (JL); Prisinzano, Thomas (T); Rice, Kenner C (KC); Baumann, Michael H (MH);

Affiliation: Clinical Psychopharmacology Section, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland 21224, USA. rrothman(-atsign-)intra.nida.nih.gov

Journal and publication information

Publication Type: Journal Article

Journal: Synapse (New York, N.Y.) (Synapse), published in United States. (Language: eng)

Reference: 2003-Dec; vol 50 (issue 3) : pp 233-9

Dates: Created 2003/09/29; Completed 2004/01/06; Revised 2005/11/17;

PMID: 14515341, status: MEDLINE (last retrieval date: 2/18/2009, IMS Date: )

Sourced from the National Library of Medicine. Abstract text and other information may be subject to copyright.

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MeSH headings (categories)

This article was linked to the MESH Headings shown below.

Animals Blotting, Western Carrier Proteins - drug effects; metabolism Fenfluramine - administration & dosage; toxicity Hydroxyindoleacetic Acid - metabolism Male Membrane Glycoproteins - drug effects; metabolism Membrane Transport Proteins

Nerve Tissue Proteins Prosencephalon - drug effects; metabolism Rats Rats, Sprague-Dawley Serotonin - metabolism Serotonin Agents - administration & dosage; toxicity Serotonin Plasma Membrane Transport Proteins p-Chloroamphetamine - administration & dosage; toxicity

Associated Chemicals: Carrier Proteins (0) ; Membrane Glycoproteins (0) ; Membrane Transport Proteins (0) ; Nerve Tissue Proteins (0) ; Serotonin Agents (0) ; Serotonin Plasma Membrane Transport Proteins (0) ; Slc6a4 protein, rat (0) ; Fenfluramine (458-24-2) ; Serotonin (50-67-9) ; Hydroxyindoleacetic Acid (54-16-0) ; p-Chloroamphetamine (64-12-0)

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