Substituted amphetamines that produce long-term serotonin depletion in rat brain ("neurotoxicity") do not decrease serotonin transporter protein expression.
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.
Rothman
Richard B
RB
Clinical Psychopharmacology Section, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland 21224, USA. rrothman@intra.nida.nih.gov
Jayanthi
Subramaniam
S
Cadet
Jean L
JL
Wang
Xiaoying
X
Dersch
Christina M
CM
Baumann
Michael H
MH
D000662:Amphetamines / Q000633:toxicity*; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D008297:Male; D008562:Membrane Glycoproteins / Q000096:biosynthesis* / Q000235:genetics; D026901:Membrane Transport Proteins / Q000096:biosynthesis* / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000096:biosynthesis* / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000378:metabolism*; D050486:Serotonin Plasma Membrane Transport Proteins; D013995:Time
D000662:Amphetamines; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D050486:Serotonin Plasma Membrane Transport Proteins; C493232:Slc6a4 protein, rat; D012701:Serotonin