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Substituted Amphetamines That Produce Long-Term Serotonin Depletion in Rat Brain ("Neurotoxicity") Do Not Decrease Serotonin Transporter Protein Expression
aClinical Psychopharmacology Section, bMolecular Neuropsychiatry Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland 21224, USA
Note: This article is a written summary of our recent oral presentation at the ISN/APSN Satellite Meeting. It is based on a paper that has now been published.1 Address for correspondence: Richard B. Rothman, M.D., Ph.D., Clinical Psychopharmacology Section, Intramural Research Program, NIDA, NIH, 5500 Nathan Shock Drive, Baltimore, MD 21224. Voice: 410-550-1487; fax: 410-550-2997. rrothman{at}intra.nida.nih.gov Ann. N.Y. Acad. Sci. 1025: 151-161 (2004).
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.
Key Words: serotonin transporter • fenfluramine • parachloroamphetamine • neurotoxicity • amphetamine
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