Serotonin neurotoxicity in rats after combined treatment with a dopaminergic agent followed by a nonneurotoxic 3,4-methylenedioxymethamphetamine (MDMA) analogue.
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.
Johnson
M P
MP
Department of Pharmacology and Toxicology, School of Pharmacy and Pharmacal Sciences, Purdue University, West Lafayette, IN 47907.
Huang
X M
XM
Nichols
D E
DE
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D015104:3,4-Methylenedioxyamphetamine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000633:toxicity; D000661:Amphetamine / Q000008:administration & dosage / Q000633:toxicity; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D015259:Dopamine Agents / Q000008:administration & dosage / Q000633:toxicity*; D006719:Homovanillic Acid / Q000378:metabolism; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D007189:Indans / Q000008:administration & dosage / Q000633:toxicity*; D018817:N-Methyl-3,4-methylenedioxyamphetamine; D051381:Rats; D012701:Serotonin / Q000378:metabolism*
D015259:Dopamine Agents; D007189:Indans; C066678:5,6-methylenedioxy-2-aminoindane; D015102:3,4-Dihydroxyphenylacetic Acid; D012701:Serotonin; D015104:3,4-Methylenedioxyamphetamine; D006897:Hydroxyindoleacetic Acid; D000661:Amphetamine; D018817:N-Methyl-3,4-methylenedioxyamphetamine; D004298:Dopamine; D006719:Homovanillic Acid