Subjective and neurochemical effects of modafinil in mice

Modafinil, a drug approved for treatment of narcolepsy, is reportedly efficacious in off‐label tests for other disorders, such as ADHD and stimulant abuse. Modafinil inhibits the dopamine (DA) transporter (DAT), and has effects on several neurotransmitters, which may relate to its therapeutic efficacy. We tested if its actions at the DAT produce stimulant‐like effects on DA levels in Swiss Webster mice implanted with microdialysis probes in nucleus accumbens shell (NAS) or core (NAC), and on subjective responses in mice discriminating 10 mg/kg cocaine from saline, i.p. Modafinil (30, 100, 300 mg/kg, i.p.) significantly increased NAS and NAC DA levels. Both 100 and 300 mg/kg induced a rapid (280 and 250% of basal values, respectively within the first hour) and long‐lasting (> 6 hours) increase in NAS DA levels. In NAC, 300 mg/kg produced the greatest stimulation (250% 2–3 hrs after injection) with a slow onset, and less stimulation in the next two hrs. Over a similar dose range, modafinil produced cocaine‐like subjective effects when administered 60‐, but not 5‐min before testing. The results suggest a stimulant‐like profile for modafinil, with lower efficacy than cocaine, and a longer duration of action. These features may limit the abuse liability of modafinil, and may contribute to its potential therapeutic effects as a treatment for stimulant abuse or other psychiatric disorders. Supported by NIDA‐IRP funds