TY - JOUR
T1 - Behavioral and neurochemical consequences of long-term intravenous self-administration of MDMA and its enantiomers by rhesus monkeys
AU - Fantegrossi, William E.
AU - Woolverton, William L.
AU - Kilbourn, Michael
AU - Sherman, Phillip
AU - Yuan, Jie
AU - Hatzidimitriou, George
AU - Ricaurte, George A.
AU - Woods, James H.
AU - Winger, Gail
N1 - Funding Information:
Expert technical assistance with the monkey self-administration experiments was provided by Debbie Huntzinger, Sarah Pilkington, and Jolan Terner at the University of Michigan. The authors express their gratitude to Kyle Kuzspit and Leslie Doherty at the University of Michigan PET facility for their skilled aid in the conduct of the imaging procedures. Insightful comments on an earlier draft of this manuscript (presented as a chapter in the doctoral thesis of WEF) were provided by Theresea Lee and Terry Robinson at the University of Michigan Department of Psychology, and by Una McCann at the Johns Hopkins Medical Institutions. These studies were supported by USPHS Grants DA09161, DA05923, DA05707, and DA00206.
PY - 2004/7
Y1 - 2004/7
N2 - 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 overa 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.
AB - 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 overa 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.
KW - MDMA
KW - Neuroimaging
KW - Neurotoxicity
KW - Rhesus monkeys
KW - Self-administration
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U2 - 10.1038/sj.npp.1300442
DO - 10.1038/sj.npp.1300442
M3 - Article
C2 - 15039771
AN - SCOPUS:2942640253
SN - 0893-133X
VL - 29
SP - 1270
EP - 1281
JO - Neuropsychopharmacology
JF - Neuropsychopharmacology
IS - 7
ER -