Dopamine transporter-related effects of modafinil in rhesus monkeys

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.

Fig. 1

Morning (a) and evening (b) locomotor activities after modafinil injection. Activity counts were extracted and summed into hourly bins. Abscissae: time expressed in hours and plotted on an absolute linear scale. Ordinates: activity counts expressed as a percentage of the baseline activity level. An * indicates a significant (p<0.05) difference from saline baseline only; ** indicates significant differences from modafinil (3.0 mg/kg) and saline (p<0.001). Arrows represent the time of injection. Each data point represents the group mean±SEM

Fig. 2

Effects of modafinil (a) or cocaine (b) on reinstatement of cocaine-maintained behavior. Abscissae: dose of the respective drug. Ordinates: responses per second expressed as a percentage of the baseline response rate during cocaine self-administration. An * indicates a significant (p<0.05) difference from saline treatment. Each data point represents the group mean±SEM

Fig. 3

Effects of modafinil or cocaine on extracellular dopamine in the caudate nucleus of awake rhesus monkeys (n=4). Abscissae: time expressed in minutes and plotted in reference to the drug injection. Ordinates: relative dopamine concentration expressed as a percentage of the basal level prior to drug administration. An * (p<0.05) or a ** (p<0.01) indicate a significant difference from baseline levels obtained during the 60 min prior to drug administration. Arrows represent the time of injection. Each data point represents the group mean±SEM

Fig. 4

Representative time activity curves for [18F]FECNT in the caudate (cau), putamen (put) and cerebellum (cere) in rhesus monkey RLt-7. The displacement of [18F]FECNT binding, following administration of modafinil (10 mg/kg, i.v.) at 90 min, is shown with solid lines. The projected time activity curves, in the absence of modafinil administration, are shown with dotted lines. Abscissae: time expressed in minutes and plotted in reference to the injection of the radiotracer. Ordinates: radioactivity counts decay corrected and expressed on an absolute linear scale. Each data point represents the value obtained from a single representative subject