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Substituted amphetamines that produce long-term serotonin depletion in rat brain ("neurotoxicity") do not decrease serotonin transporter protein expression.
Ann N Y Acad Sci 2004; 1025:151-61AN

Abstract

Administration of high-dose D-fenfluramine (D-FEN) or parachloroamphetamine (PCA) produces 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 few studies have measured SERT protein levels. Thus, 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 to 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 D-FEN- and PCA-induced decreases in tissue 5-HT and SERT binding sites reflect neuroadaptive changes rather than neurotoxic effects.

Authors+Show Affiliations

Clinical Psychopharmacology Section, Intramural Research Program, 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 available

Pub Type(s)

Comparative Study
Journal Article

Language

eng

PubMed ID

15542713

Citation

Rothman, Richard B., et al. "Substituted Amphetamines That Produce Long-term Serotonin Depletion in Rat Brain ("neurotoxicity") Do Not Decrease Serotonin Transporter Protein Expression." Annals of the New York Academy of Sciences, vol. 1025, 2004, pp. 151-61.
Rothman RB, Jayanthi S, Cadet JL, et al. Substituted amphetamines that produce long-term serotonin depletion in rat brain ("neurotoxicity") do not decrease serotonin transporter protein expression. Ann N Y Acad Sci. 2004;1025:151-61.
Rothman, R. B., Jayanthi, S., Cadet, J. L., Wang, X., Dersch, C. M., & Baumann, M. H. (2004). Substituted amphetamines that produce long-term serotonin depletion in rat brain ("neurotoxicity") do not decrease serotonin transporter protein expression. Annals of the New York Academy of Sciences, 1025, pp. 151-61.
Rothman RB, et al. Substituted Amphetamines That Produce Long-term Serotonin Depletion in Rat Brain ("neurotoxicity") Do Not Decrease Serotonin Transporter Protein Expression. Ann N Y Acad Sci. 2004;1025:151-61. PubMed PMID: 15542713.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Substituted amphetamines that produce long-term serotonin depletion in rat brain ("neurotoxicity") do not decrease serotonin transporter protein expression. AU - Rothman,Richard B, AU - Jayanthi,Subramaniam, AU - Cadet,Jean L, AU - Wang,Xiaoying, AU - Dersch,Christina M, AU - Baumann,Michael H, PY - 2004/11/16/pubmed PY - 2005/2/19/medline PY - 2004/11/16/entrez SP - 151 EP - 61 JF - Annals of the New York Academy of Sciences JO - Ann. N. Y. Acad. Sci. VL - 1025 N2 - Administration of high-dose D-fenfluramine (D-FEN) or parachloroamphetamine (PCA) produces 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 few studies have measured SERT protein levels. Thus, 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 to 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 D-FEN- and PCA-induced decreases in tissue 5-HT and SERT binding sites reflect neuroadaptive changes rather than neurotoxic effects. SN - 0077-8923 UR - https://www.unboundmedicine.com/medline/citation/15542713/Substituted_amphetamines_that_produce_long_term_serotonin_depletion_in_rat_brain__"neurotoxicity"__do_not_decrease_serotonin_transporter_protein_expression_ L2 - https://onlinelibrary.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0077-8923&date=2004&volume=1025&spage=151 DB - PRIME DP - Unbound Medicine ER -