Serotonin neurotoxicity in rats after combined treatment with a dopaminergic agent followed by a nonneurotoxic 3,4-methylenedioxymethamphetamine (MDMA) analogue

Pharmacol Biochem Behav. 1991 Dec;40(4):915-22. doi: 10.1016/0091-3057(91)90106-c.


There is increasing evidence linking dopamine (DA) to the long-term serotonergic (5-HT) neurotoxic effects of certain substituted amphetamines such as 3,4-methylenedioxymethamphetamine (MDMA). The present study was undertaken to examine the importance of DA metabolism, uptake inhibition and release in the long-term effects of these drugs by combining various dopaminergic agents with an analogue of MDMA that had low neurotoxic liability, namely 5,6-methylenedioxy-2-aminoindan (MDAI). Monoamine and metabolite levels and the number of 5-HT uptake sites (using [3H]paroxetine binding) were determined 3 hours or 1 week after treatments. Combining the monoamine oxidase inhibitors, clorgyline (MAOA selective) or deprenyl (MAOB selective) with MDAI did not result in any long-term reductions of serotonergic markers. Similarly, combining the DA uptake inhibitor GBR-12909 with MDAI did not result in any long-term changes in monoamine levels at 1 week. In contrast, a single pretreatment of posttreatment with the nonvesicular DA releaser S-amphetamine and MDAI resulted in small but significant long-term changes in monoamine levels. More importantly, if a subacute dosing regimen (every 12 hours for 4 days) was utilized, the combination of S-amphetamine with MDAI resulted in a marked long-term decrease in the levels of cortical, hippocampal and striatal 5-HT, 5-HIAA and the number of 5-HT uptake sites. The results are discussed in terms of the significance of DA and especially nonvesicular DA release in the long-term effects of MDMA-like drugs.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 3,4-Dihydroxyphenylacetic Acid / metabolism
  • 3,4-Methylenedioxyamphetamine / administration & dosage
  • 3,4-Methylenedioxyamphetamine / analogs & derivatives
  • 3,4-Methylenedioxyamphetamine / toxicity
  • Amphetamine / administration & dosage
  • Amphetamine / toxicity
  • Animals
  • Brain / drug effects*
  • Brain / metabolism
  • Dopamine / metabolism
  • Dopamine Agents / administration & dosage
  • Dopamine Agents / toxicity*
  • Homovanillic Acid / metabolism
  • Hydroxyindoleacetic Acid / metabolism
  • Indans / administration & dosage
  • Indans / toxicity*
  • N-Methyl-3,4-methylenedioxyamphetamine
  • Rats
  • Serotonin / metabolism*


  • Dopamine Agents
  • Indans
  • 5,6-methylenedioxy-2-aminoindane
  • 3,4-Dihydroxyphenylacetic Acid
  • Serotonin
  • 3,4-Methylenedioxyamphetamine
  • Hydroxyindoleacetic Acid
  • Amphetamine
  • N-Methyl-3,4-methylenedioxyamphetamine
  • Dopamine
  • Homovanillic Acid