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Substituted amphetamines that produce long-term serotonin depletion in rat brain ("neurotoxicity") do not decrease

Richard B Rothman1, Subramaniam Jayanthi, Jean L Cadet

  • 1Clinical Psychopharmacology Section, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland 21224, USA. rrothman@intra.nida.nih.gov

Annals of the New York Academy of Sciences
|November 16, 2004
PubMed
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This summary is machine-generated.

High-dose D-fenfluramine (D-FEN) and parachloroamphetamine (PCA) decrease serotonin transporter (SERT) binding and serotonin (5-HT) levels. However, these drug treatments did not significantly alter SERT protein levels, suggesting neuroadaptation rather than neurotoxicity.

Area of Science:

  • Neuroscience
  • Pharmacology
  • Toxicology

Background:

  • High-dose D-fenfluramine (D-FEN) and parachloroamphetamine (PCA) are known to cause long-lasting reductions in serotonin transporter (SERT) binding and serotonin (5-HT) levels in the rat forebrain.
  • These observed changes have been historically interpreted as evidence of 5-HT neurotoxicity.
  • However, a comprehensive assessment of SERT protein levels in response to these drugs has been limited.

Purpose of the Study:

  • To investigate the effects of high-dose D-FEN and PCA on SERT protein levels and SERT binding density.
  • To differentiate between neurotoxic effects and neuroadaptive changes induced by D-FEN and PCA.

Main Methods:

  • Rats were administered high doses of D-FEN or PCA following a neurotoxic dosing regimen.

Related Experiment Videos

  • SERT binding density was measured using ligand binding assays in caudate and whole brain minus caudate homogenates.
  • SERT protein levels were quantified using Western blot analysis.
  • Tissue levels of 5-HT and 5-HIAA were measured, and glial fibrillary acidic protein (GFAP) expression was assessed as an indicator of neuronal damage.

    • Main Results:

    • Both D-FEN and PCA significantly decreased SERT binding density by 30-60% in both tissues at 2 days and 2 weeks post-administration.
    • Tissue 5-HT and 5-HIAA levels were profoundly reduced in the frontal cortex following D-FEN and PCA administration.
    • Despite significant reductions in SERT binding and 5-HT levels, D-FEN did not alter SERT protein expression. PCA administration resulted in a modest ~20% decrease in SERT protein in the caudate at the 2-day time point.
    • No changes in GFAP expression were observed, indicating a lack of significant neuronal damage.

    Conclusions:

    • The decreases in 5-HT tissue levels and SERT binding sites induced by D-FEN and PCA are likely due to neuroadaptive changes in the serotonin system.
    • These findings challenge the prevailing view of D-FEN and PCA as purely neurotoxic agents at the doses studied.
    • The data suggest that the serotonin system can undergo significant adaptive responses to drug exposure without overt neuronal damage.