Document Detail


Behavioral and neurochemical consequences of long-term intravenous self-administration of MDMA and its enantiomers by rhesus monkeys.
MedLine Citation:
PMID:  15039771     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
William E Fantegrossi; William L Woolverton; Michael Kilbourn; Phillip Sherman; Jie Yuan; George Hatzidimitriou; George A Ricaurte; James H Woods; Gail Winger
Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology     Volume:  29     ISSN:  0893-133X     ISO Abbreviation:  Neuropsychopharmacology     Publication Date:  2004 Jul 
Date Detail:
Created Date:  2004-06-21     Completed Date:  2004-08-02     Revised Date:  2011-05-18    
Medline Journal Info:
Nlm Unique ID:  8904907     Medline TA:  Neuropsychopharmacology     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1270-81     Citation Subset:  IM    
Copyright Information:
Copyright 2004 Nature Publishing Group
Affiliation:
Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI 48101-0632, USA. billfan@umich.edu
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MeSH Terms
Descriptor/Qualifier:
Animals
Behavior, Animal / drug effects*
Biogenic Monoamines / metabolism
Brain / blood supply,  drug effects*
Brain Chemistry / drug effects*
Brain Mapping
Central Nervous System Stimulants / administration & dosage
Chromatography, High Pressure Liquid / methods
Cocaine / pharmacology
Dopamine Uptake Inhibitors / pharmacology
Dose-Response Relationship, Drug
Electrochemistry / methods
Infusions, Intravenous / methods
Macaca mulatta
Methamphetamine / administration & dosage
N-Methyl-3,4-methylenedioxyamphetamine / administration & dosage*,  chemistry
ROC Curve
Radioligand Assay / methods
Self Administration / methods
Serotonin Agents / administration & dosage*,  chemistry
Stereoisomerism
Tetrabenazine / analogs & derivatives*,  pharmacokinetics
Tissue Distribution
Tomography, Emission-Computed / methods
Tritium / pharmacokinetics
Grant Support
ID/Acronym/Agency:
DA00206/DA/NIDA NIH HHS; DA05707/DA/NIDA NIH HHS; DA05923/DA/NIDA NIH HHS; DA09161/DA/NIDA NIH HHS
Chemical
Reg. No./Substance:
0/Biogenic Monoamines; 0/Central Nervous System Stimulants; 0/Dopamine Uptake Inhibitors; 0/Serotonin Agents; 10028-17-8/Tritium; 3466-75-9/dihydrotetrabenazine; 42542-10-9/N-Methyl-3,4-methylenedioxyamphetamine; 50-36-2/Cocaine; 537-46-2/Methamphetamine; 58-46-8/Tetrabenazine
Comments/Corrections
Comment In:
Neuropsychopharmacology. 2004 Oct;29(10):1940-1; author reply 1942   [PMID:  15383828 ]

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