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Dopamine transporter-related effects of modafinil in rhesus monkeys

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Abstract

Rationale

Modafinil is currently used as a treatment for daytime sleepiness.

Objectives

The objectives of this study were to explore the dopamine transporter (DAT)-related effects of modafinil on behavior and in vivo neurochemistry in rhesus monkeys (Macaca mulatta).

Methods

The effects of modafinil (3.0–10 mg/kg, i.v.) were evaluated on locomotor activity, reinstatement of cocaine-maintained behavior, extracellular dopamine levels in the caudate nucleus, and DAT occupancy in the dorsal striatum. Eight subjects were fitted with a collar-mounted activity monitor to evaluate sleep-activity cycles, with 4 days of baseline recording preceding an injection of saline or modafinil (3.0–10 mg/kg). The effects of modafinil (3.0–10 mg/kg) and cocaine (0.3 mg/kg) on reinstatement of behavior that was previously maintained under a second-order schedule of i.v. cocaine delivery were tested in a separate group of subjects (n = 6). Finally, the effects of modafinil (3.0–10 mg/kg) on extracellular dopamine levels and DAT occupancy in vivo were characterized using microdialysis and positron emission tomography, respectively, in a within-subjects design (n = 4).

Results

Modafinil significantly increased nighttime locomotor activity and reinstated cocaine-maintained behavior but did not affect daytime locomotor activity. Modafinil significantly increased striatal extracellular dopamine levels at a dose that resulted in DAT occupancy of 64.4% (putamen) and 60.2% (caudate).

Conclusion

The behavioral and in vivo dopaminergic effects of modafinil are consistent with the profile of a low potency DAT inhibitor and may indicate potential for abuse at high doses.

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Acknowledgments

The authors express their gratitude to Lisa Neidert and Juliet Brown for capable technical assistance; Jon Nye and John Votaw for the help with PET analysis. We also thank Paul Chen for his aid in the conduct of the imaging procedures. The research was supported by USPHS Grants DA10344 (LLH), DA00517 (LLH), RR00165 (Yerkes National Primate Research Center), and Associacao Fundo de Incentivo a Psicofarmacologia (AFIP), FAPESP (98/14303) and CNPq (MLA, ST).

Conflict of interest

The authors declared no conflict of interest.

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Authors and Affiliations

  1. Yerkes National Primate Research Center, Emory University, 954 Gatewood Rd, Atlanta, GA, 30329, USA

    Monica L. Andersen, Eileen Kessler, Kevin S. Murnane, Jessica C. McClung & Leonard L. Howell

  2. Department of Psychobiology, Universidade Federal de São Paulo (UNIFESP), São Paulo, SP, Brazil

    Monica L. Andersen & Sergio Tufik

  3. Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA, USA

    Leonard L. Howell

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  1. Monica L. Andersen
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  2. Eileen Kessler
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  4. Jessica C. McClung
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  5. Sergio Tufik
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  6. Leonard L. Howell
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Correspondence to Leonard L. Howell.

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Andersen, M.L., Kessler, E., Murnane, K.S. et al. Dopamine transporter-related effects of modafinil in rhesus monkeys. Psychopharmacology 210, 439–448 (2010). https://doi.org/10.1007/s00213-010-1839-2

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  • DOI: https://doi.org/10.1007/s00213-010-1839-2

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