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).Correspondence to: Leonard L. Howell, lhowell@emory.edu. Conflict of interestThe authors declared no conflict of interest. NIH Public AccessAuthor Manuscript Psychopharmacology (Berl). Author manuscript; available in PMC 2011 June 1. Results-Modafinil significantly increased nighttime locomotor activity and reinstated cocainemaintained 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.

Selective serotonin re-uptake inhibitors (SSRIs), which are used commonly to treat anxiety disorders, have characteristic anxiogenic effects following acute administration. Treatment with anxiolytic benzodiazepines (BZs) may reduce these effects, although little is known about potential drug interactions. Our study evaluated acute anxiogenic–like effects of SSRIs, alone and combined with a BZ. Adult male BALB/c mice received fluoxetine (3.0–30.0 mg/kg, i.p.) or citalopram (3.0–30.0 mg/kg, i.p.) alone or in combination with diazepam (0.3–10.0 mg/kg, i.p.), after which they were evaluated with the light/dark and open-field tests for anxiogenesis/anxiolysis. In addition, release of the stress hormone corticosterone was assessed following combined SSRI/BZ administration. In the light/dark and open-field tests, acute SSRIs produced a behavioral profile consistent with anxiogenesis, while diazepam produced an anxiolytic-like profile. Pre-treatment with diazepam (0.3–10 mg/kg) reversed the effects of an anxiogenic-like dose of an SSRI (18 mg/kg fluoxetine, 30 mg/kg citalopram) in both light/dark and open-field tests. Diazepam, fluoxetine or citalopram, and their combination all significantly increased plasma corticosterone levels to the same degree. These findings suggest that a BZ-type drug can attenuate acute anxiogenic-like effects of an SSRI via a mechanism independent of corticosterone regulation.

Modafinil is currently used as a treatment for excessive daytime sleepiness. Increasing evidence suggests modafinil affects the dopamine transporter. Therefore, we examined the effects of modafinil (10 mg/kg; i.v.) on daytime locomotor activity, cocaine self‐administration, reinstatement of cocaine‐maintained behavior, and extracellular dopamine levels. Locomotor activity was measured in the home cage using Actiwatch telemetry, with four days of baseline recording preceding a morning injection. Administration of modafinil did not significantly increase daytime locomotor activity. Monkeys self‐administered cocaine under a second order, fixed ratio 20 schedule; pretreatment with modafinil did not have a significant effect on cocaine self‐administration. Cocaine maintained responding was then extinguished and extinction level responding maintained for a minimum of two days before priming with modafinil. Modafinil was able to significantly reinstate extinguished cocaine‐maintained behavior. Finally, dopamine levels following modafinil administration were measured using in vivo microdialysis followed by sample analysis using high performance liquid chromatography. Modafinil significantly increased dopamine overflow within the caudate nucleus approximately 20 minutes after injection. PET imaging will determine DAT occupancy associated with behavioral and neurochemical effects. Modafinil did not appear to have behavioral stimulant effects at 10 mg/kg, but at this dose does appear to have dopaminergic effects as measured by in vivo neurochemistry and cocaine reinstatement assays.