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Role of dopamine transporters in the behavioral effects of 3,4-methylenedioxymethamphetamine (MDMA) in nonhuman primates

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Abstract

Rationale

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 5HT2A 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.

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Acknowledgments

Expert technical assistance with all nonhuman primate procedures was provided by Tango Howard, Carol Nichols, Jodi Godfrey, and Lisa Neidert at the Yerkes National Primate Research Center. The authors express their gratitude to Larry Williams at the Emory University PET Center for his skilled aid in the conduct of the imaging procedures. These studies were supported by USPHS Grants DA10344 (LLH), DA12514 (LLH), DA00517 (LLH), DA20645 (WEF), RR00165 (LLH and WEF), and RR020146 (WEF).

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Authors and Affiliations

  1. Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, AR, USA

    William E. Fantegrossi

  2. Division of Neuroscience, Yerkes National Primate Research Center, Emory University, 954 Gatewood Road NE, Atlanta, GA, 30329, USA

    William E. Fantegrossi, Rayna M. Bauzo, Daniel M. Manvich, Jose C. Morales & Leonard L. Howell

  3. Department of Radiology, Emory University School of Medicine, Atlanta, GA, USA

    John R. Votaw & Mark M. Goodman

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  1. William E. Fantegrossi
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  2. Rayna M. Bauzo
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  3. Daniel M. Manvich
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  4. Jose C. Morales
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  5. John R. Votaw
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  7. Leonard L. Howell
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Correspondence to Leonard L. Howell.

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Fantegrossi, W.E., Bauzo, R.M., Manvich, D.M. et al. Role of dopamine transporters in the behavioral effects of 3,4-methylenedioxymethamphetamine (MDMA) in nonhuman primates. Psychopharmacology 205, 337–347 (2009). https://doi.org/10.1007/s00213-009-1545-0

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  • DOI: https://doi.org/10.1007/s00213-009-1545-0

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