Oral administration of 3,4-methylenedioxymethamphetamine (MDMA) produces selective serotonergic depletion in the nonhuman primate.
MDMA (3,4-methylenedioxymethamphetamine) has been reported to produce serotonergic depletion in nonhuman primates at doses as low as 2.5 mg/kg (1-2 times the typical human dose). The current study evaluated the dose-response relationships of MDMA (1.25-20.0 mg/kg) using regional concentrations of serotonin (5-HT) and its metabolite, 5-hydroxyindoleacetic acid (5-HIAA), and home cage behavior as endpoints. Adult female rhesus monkeys (n = 16) were treated orally with 0, 1.25, 2.5, or 20.0 mg/kg MDMA twice daily for 4 consecutive days. Eighteen behaviors were measured in the home cage prior to, during, and after MDMA treatment. One month after the last dose, the animals were sacrificed and brains dissected into several regions for neurochemical analyses. 5-HT and 5-HIAA were analyzed via HPLC/EC. The lower doses of MDMA (1.25 and 2.5 mg/kg) did not significantly alter 5-HT or 5-HIAA concentrations in any brain region except hippocampus in which 5-HT concentrations were decreased after 2.5 mg/kg. MDMA at 20.0 mg/kg significantly decreased 5-HT and 5-HIAA concentrations in several cortical and midbrain structures. However, 5-HT and 5-HIAA concentrations in brain stem and hypothalamus were not significantly altered after any dose of MDMA. Combined with previous data from this laboratory, these results indicate that the decreased concentrations of 5-HT and 5-HIAA in selected brain regions show a selective dose-response relationship for MDMA-induced neurotoxicity as measured by serotonergic depletion in the nonhuman primate.
Ali
S F
SF
Division of Neurotoxicology, National Center for Toxicological Research, Jefferson, AR 72079-9502.
Newport
G D
GD
Scallet
A C
AC
Binienda
Z
Z
Ferguson
S A
SA
Bailey
J R
JR
Paule
M G
MG
Slikker
W
W
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D015104:3,4-Methylenedioxyamphetamine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D000284:Administration, Oral; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D006719:Homovanillic Acid / Q000378:metabolism; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D008253:Macaca mulatta; D018817:N-Methyl-3,4-methylenedioxyamphetamine; D012701:Serotonin / Q000378:metabolism*
D015102:3,4-Dihydroxyphenylacetic Acid; D012701:Serotonin; D015104:3,4-Methylenedioxyamphetamine; D006897:Hydroxyindoleacetic Acid; D018817:N-Methyl-3,4-methylenedioxyamphetamine; D004298:Dopamine; D006719:Homovanillic Acid