In vivo analysis of serotonin clearance in rat hippocampus reveals that repeated administration of p-methoxyamphetamine (PMA), but not 3,4-methylenedioxymethamphetamine (MDMA), leads to long-lasting deficits in serotonin transporter function.
p-Methoxyamphetamine (PMA) has been implicated in fatalities as a result of 'ecstasy' (MDMA) overdose worldwide. Like MDMA, acute effects are associated with marked changes in serotonergic neurotransmission, but the long-term effects of PMA are poorly understood. The aim of this study was to determine the effect of repeated PMA administration on in vitro measures of neurodegeneration: serotonin (5-HT) uptake, 5-HT transporter (SERT) density and 5-HT content in the hippocampus, and compare with effects on in vivo 5-HT clearance. Male rats received PMA, MDMA (4 or 15 mg/kg s.c., twice daily) or vehicle for 4 days and 2 weeks later indices of SERT function were measured. [(3)H]5-HT uptake into synaptosomes and [(3)H]cyanoimipramine binding to the SERT were significantly reduced by both PMA and MDMA treatments. 5-HT content was reduced in MDMA-, but not PMA-treatment. In contrast, clearance of locally applied 5-HT measured in vivo by chronoamperometry was only reduced in rats treated with 15 mg/kg PMA. The finding that 5-HT clearance in vivo was unaltered by MDMA treatment suggests that in vitro measures of 5-HT axonal degeneration do not necessarily predict potential compensatory mechanisms that maintain SERT function under basal conditions.
Callaghan
Paul D
PD
Department of Physiology, The University of Texas Health Science Center at San Antonio, TX 78229-3900, USA.
Owens
W Anthony
WA
Javors
Martin A
MA
Sanchez
Teresa A
TA
Jones
David J
DJ
Irvine
Rodney J
RJ
Daws
Lynette C
LC
D000662:Amphetamines / Q000494:pharmacology*; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects / Q000502:physiology; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D008657:Metabolic Clearance Rate / Q000187:drug effects / Q000502:physiology; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000494:pharmacology*; D017729:Presynaptic Terminals / Q000187:drug effects / Q000378:metabolism; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000378:metabolism* / Q000493:pharmacokinetics; D018490:Serotonin Agents / Q000494:pharmacology; D050486:Serotonin Plasma Membrane Transport Proteins / Q000187:drug effects / Q000378:metabolism*; D013574:Synaptosomes / Q000737:chemistry / Q000378:metabolism; D014855:Wallerian Degeneration / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology
D000662:Amphetamines; D018490:Serotonin Agents; D050486:Serotonin Plasma Membrane Transport Proteins; D012701:Serotonin; D018817:N-Methyl-3,4-methylenedioxyamphetamine; C100230:4-methoxyamphetamine