Role of dopamine transporters in the behavioral effects of 3,4-methylenedioxymethamphetamine (MDMA) in nonhuman primates.
BACKGROUND
The interoceptive and reinforcing effects of 3,4-methylenedioxymethamphetamine (MDMA) are similar to those of psychostimulants, but the role of dopamine in the behavioral effects of MDMA is not well documented, especially in primates.


OBJECTIVE
The aim of this study was to assess the role of dopamine in the behavioral effects of MDMA in two nonhuman primate species.


METHODS
The behavioral effects of MDMA, with and without serotonergic or dopaminergic pretreatments, were studied in squirrel monkeys trained to respond under a fixed-interval schedule of stimulus termination; effects on caudate dopamine levels were studied in a separate group of squirrel monkeys using in vivo microdialysis. Positron emission tomography neuroimaging with the dopamine transporter (DAT) ligand [18F]FECNT was used to determine DAT occupancy by MDMA in rhesus monkeys.


RESULTS
MDMA (0.5-1.5 mg/kg) did not induce behavioral stimulant effects, but the highest dose of MDMA suppressed responding. Pretreatment with fluoxetine (3.0 mg/kg) or the selective 5HT(2A) antagonist M100907 (0.03-0.3 mg/kg) attenuated the rate suppressing effects of MDMA. In contrast, pretreatment with the selective dopamine transporter inhibitor RTI-177 (0.1 mg/kg) did not alter the rate suppressing effects of MDMA. Administration of MDMA at a dose that suppressed operant behavior had negligible effects on extracellular dopamine. The percent DAT occupancy of MDMA at a dose that suppressed operant behavior also was marginal and reflected low in vivo potency for DAT binding.


CONCLUSIONS
Collectively, these results indicate that behaviorally relevant doses of MDMA do not induce behavioral stimulant or dopamine transporter-mediated effects in nonhuman primates.
Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
William E
WE
Fantegrossi
Rayna M
RM
Bauzo
Daniel M
DM
Manvich
Jose C
JC
Morales
John R
JR
Votaw
Mark M
MM
Goodman
Leonard L
LL
Howell
D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001921:Brain / Q000000981:diagnostic imaging / Q000187:drug effects; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D003216:Conditioning, Operant / Q000187:drug effects / Q000502:physiology; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D055664:Electrochemical Techniques / Q000379:methods; D005260:Female; D005462:Fluorine Radioisotopes / Q000378:metabolism; D005464:Fluorobenzenes / Q000494:pharmacology; D006213:Hallucinogens / Q000494:pharmacology*; D008253:Macaca mulatta; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008694:Methamphetamine / Q000494:pharmacology; D017551:Microdialysis / Q000379:methods; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000494:pharmacology*; D009662:Nortropanes / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology; D049268:Positron-Emission Tomography / Q000379:methods; D012055:Reinforcement Schedule; D012453:Saimiri; D012702:Serotonin Antagonists / Q000494:pharmacology; D014326:Tropanes / Q000494:pharmacology
C410211:2-carbomethoxy-3-(4-chlorophenyl)-8-(2-fluoroethyl)nortropane; C095429:3-(4'-chlorophenyl)-2-(3'-phenylisoxazol-5'-yl)tropane; D000697:Central Nervous System Stimulants; D050483:Dopamine Plasma Membrane Transport Proteins; D005462:Fluorine Radioisotopes; D005464:Fluorobenzenes; D006213:Hallucinogens; D009662:Nortropanes; D010880:Piperidines; D012702:Serotonin Antagonists; D014326:Tropanes; D008694:Methamphetamine; C079049:volinanserin; D018817:N-Methyl-3,4-methylenedioxyamphetamine