Dopamine transporter-related effects of modafinil in rhesus monkeys

• Authors: Monica L. Andersen, Emory University; Eileen Kessler, Emory University; Kevin Murnane, Emory University; Jessica C. McClung, Emory University; Sergio Tufik, Universidade Federal de São Paulo; Leonard L. Howell, Emory University
• Journal Title: Psychopharmacology
• Volume: Volume 210, Number 3
• Publisher: Springer Verlag (Germany) | 2010-06-01, Pages 439-448
• Type of Work: Article | Post-print: After Peer Review
• Publisher DOI: http://doi.org/10.1007/s00213-010-1839-2
• Subjects: Health Sciences, Pharmacology; Psychology, Experimental; Chemistry, Biochemistry
• Keywords: Modafinil; Cocaine; Reinstatement; Nonhuman primate; PET; In vivo microdialysis; Dopamine; Imaging; Sleep

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.