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

Michael P. Johnson, Xuemei Huang, David E. Nichols

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27 Citations (Scopus)

Abstract

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 or 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.

Original languageEnglish (US)
Pages (from-to)915-922
Number of pages8
JournalPharmacology, Biochemistry and Behavior
Volume40
Issue number4
DOIs
StatePublished - Dec 1991

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N-Methyl-3,4-methylenedioxyamphetamine
Dopamine Agents
Rats
Dopamine
Serotonin
Amphetamine
Dopamine Uptake Inhibitors
Clorgyline
Enzyme inhibition
Selegiline
Amphetamines
Corpus Striatum
Paroxetine
Hydroxyindoleacetic Acid
Monoamine Oxidase Inhibitors
Metabolites
Metabolism
Pharmaceutical Preparations
5,6-methylenedioxy-2-aminoindane

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Toxicology
  • Pharmacology
  • Clinical Biochemistry
  • Biological Psychiatry
  • Behavioral Neuroscience

Cite this

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title = "Serotonin neurotoxicity in rats after combined treatment with a dopaminergic agent followed by a nonneurotoxic 3,4-methylenedioxymethamphetamine (MDMA) analogue",
abstract = "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 or 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.",
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T1 - Serotonin neurotoxicity in rats after combined treatment with a dopaminergic agent followed by a nonneurotoxic 3,4-methylenedioxymethamphetamine (MDMA) analogue

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AU - Huang, Xuemei

AU - Nichols, David E.

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N2 - 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 or 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.

AB - 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 or 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.

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