Behavioral and neurochemical consequences of long-term intravenous self-administration of MDMA and its enantiomers by rhesus monkeys.
The effects of self-administered 3,4-methylenedioxymethamphetamine (MDMA) on behavior and neurochemistry have not been previously studied in laboratory primates. We investigated the capacity of MDMA and its enantiomers to maintain contingent responding over an extended duration, whether any decrements in the reinforcing effects of these compounds would be observed over time, whether such decrements would be MDMA-selective, and whether any neurochemical correlates could be identified. Animals were previously trained to self-administer cocaine, then exposed to periodic substitutions of various doses of racemic MDMA and its enantiomers; full dose-effect curves were generated for each MDMA compound repeatedly over the duration of the study. After approximately 18 months of MDMA self-administration, drug exposure was halted and after at least 2 months drug abstinence, animals were scanned using positron emission tomography (PET) with the vesicular monoamine transporter (VMAT) ligand dihydrotetrabenazine (DTBZ). Shortly thereafter, animals were euthanized, brains were dissected, and samples were assayed for brain monoamines and their metabolites using high-performance liquid chromatography (HPLC), and for VMAT using DTBZ binding. The reinforcing effects of racemic and R(-)-MDMA were reduced over a long series (months) of individual self-administration access periods; the reinforcing effects of S+-MDMA were more resistant to this effect, but were attenuated for one animal. The reinforcing effects of cocaine were not altered by chronic MDMA self-administration, nor was the VMAT binding potential as assessed by PET. Further, there were no measurable decrements in serotonin (5-HT), 5-hydroxyindoleacetic acid (5-HIAA), dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC) or VMAT in any brain regions assayed. The reinforcing effects of MDMA are selectively attenuated by chronic MDMA self-administration, although this behavioral change appears to occur in the absence of any frank neurochemical correlates of toxicity.
Fantegrossi
William E
WE
Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI 48101-0632, USA. billfan@umich.edu
Woolverton
William L
WL
Kilbourn
Michael
M
Sherman
Phillip
P
Yuan
Jie
J
Hatzidimitriou
George
G
Ricaurte
George A
GA
Woods
James H
JH
Winger
Gail
G
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D015306:Biogenic Monoamines / Q000378:metabolism; D001921:Brain / Q000098:blood supply / Q000187:drug effects*; D001923:Brain Chemistry / Q000187:drug effects*; D001931:Brain Mapping; D000697:Central Nervous System Stimulants / Q000008:administration & dosage; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D003042:Cocaine / Q000494:pharmacology; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004563:Electrochemistry / Q000379:methods; D007262:Infusions, Intravenous / Q000379:methods; D008253:Macaca mulatta; D008694:Methamphetamine / Q000008:administration & dosage; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000008:administration & dosage* / Q000737:chemistry; D012372:ROC Curve; D011869:Radioligand Assay / Q000379:methods; D012646:Self Administration / Q000379:methods; D018490:Serotonin Agents / Q000008:administration & dosage* / Q000737:chemistry; D013237:Stereoisomerism; D013747:Tetrabenazine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D014018:Tissue Distribution; D014055:Tomography, Emission-Computed / Q000379:methods; D014316:Tritium / Q000493:pharmacokinetics
D015306:Biogenic Monoamines; D000697:Central Nervous System Stimulants; D018765:Dopamine Uptake Inhibitors; D018490:Serotonin Agents; D014316:Tritium; C032811:dihydrotetrabenazine; D008694:Methamphetamine; D003042:Cocaine; D018817:N-Methyl-3,4-methylenedioxyamphetamine; D013747:Tetrabenazine