Psychostimulant-like discriminative stimulus and locomotor sensitization properties of the wake-promoting agent modafinil in rodents

Abstract

The present studies assessed the potential abuse liability and likely mechanism(s) of action of the wake-promoting agent modafinil.

Methods: Experiments assessed the locomotor sensitization (LS) and discriminative stimulus (DS) properties of modafinil in mouse and rat, respectively. Comparative data were generated with a range of psychostimulants and monoamine reuptake inhibitors.

Results: Repeated administration of d-amphetamine and cocaine, psychostimulants with high abuse liability, resulted in the induction and expression of LS in mice. Bupropion and caffeine, two psychostimulants not abused in humans, were not associated with LS. GBR12909 induced LS during repeated exposure, but there was no evidence of expression of LS after acute challenge following withdrawal. In contrast, repeated administration of modafinil resulted in the expression, but not induction, of LS. d-amphetamine, but not the mu-opioid agonist morphine or the nAChR agonist nicotine, fully substituted for the cocaine DS in rats. The selective dopamine transporter (DAT) inhibitor GBR12909 fully substituted, the preferential norepinephrine transporter (NET) inhibitor desipramine partially substituted, and the selective serotonin reuptake inhibitor citalopram failed to substitute for cocaine. Modafinil fully substituted for cocaine, similar to the mixed DAT/NET inhibitor bupropion.

Conclusions: Two preclinical assays indicated potential abuse liability of modafinil; drug discrimination studies suggest DAT blockade by modafinil is a likely mechanism of action in vivo.

Figure 1. The effects of repeated administration of cocaine or d-amphetamine on locomotor activity

Panel A depicts total locomotor activity measured across 3 days of vehicle (baseline) and 5 days of cocaine (15 mg/kg) or vehicle administration (n=10/group). Panel B shows total locomotor activity measured after administration of a challenge dose of cocaine (10 mg/kg) following the 10 day wash-out period. Panel C depicts total locomotor activity measured across 3 days of vehicle (baseline) and 5 days of d-amphetamine (1.5 or 3.0 mg/kg) or vehicle (n=10/group). Panel D shows total locomotor activity measured after administration of a challenge dose of d-amphetamine (1.5 mg/kg) following the 10 day wash-out period. Asterisks (*p<0.05) indicate a significant difference compared to either Day 1 of drug exposure (Panels A and C) or the repeated vehicle-acute challenge groups (Panels B and D).

Figure 2. The effects of repeated administration of bupropion or caffeine on locomotor activity

Panel A depicts total locomotor activity measured across 3 days of vehicle (baseline) and 5 days of bupropion (10 or 20 mg/kg) or vehicle administration (n=8/group). Panel B shows total locomotor activity measured after administration of a challenge dose of bupropion (10 mg/kg) following the 10 day wash-out period. Panel C depicts total locomotor activity measured across 3 days of vehicle (baseline) and 5 days of caffeine (10 or 30 mg/kg) or vehicle administration (n=10/group). Panel D shows total locomotor activity measured after administration of a challenge dose of caffeine (10 mg/kg) following the 10 day wash-out period. Asterisks (*p<0.05) indicate a significant difference compared to either Day 1 of drug exposure (Panels A and C) or the repeated vehicle-acute challenge groups (Panels B and D).

Figure 3. The effects of repeated administration of GBR12909 and modafinil on locomotor activity

Panel A depicts total locomotor activity measured across 3 days of vehicle (baseline) and 5 days of GBR12909 (5, 15, or 25 mg/kg) or vehicle administration (n=10/group). Panel B shows locomotor activity measured after administration of a challenge dose of GBR12909 (15mg/kg) following the 10 day wash-out period. Panel C depicts total locomotor activity measured across 3 days of vehicle (baseline) and 5 days of modafinil (75 or 150 mg/kg) or vehicle treatment (n=13–14/group). Panel D shows total locomotor activity measured after administration of a challenge dose of modafinil (75 mg/kg) following the 10 day wash-out period. Asterisks (*p<0.05) indicate a significant difference compared to either Day 1 of drug exposure (Panels A and C) or the repeated vehicle-acute challenge groups (Panels B and D).

Figure 4. Discriminative stimulus properties of d-amphetamine, nicotine, morphine GBR12909, citalopram, desipramine, bupropion and modafinil in cocaine-trained rats

The graphs depict the effects of d-amphetamine (n=5), nicotine (n=6) and morphine (n=6; Panels A and B), GBR12909 (n=7), citalopram (n=8), desipramine (n=8), bupropion (n=9) and modafinil (n=9; Panels C and D), on cocaine-appropriate responding and response rates in rats trained to discriminate cocaine (10 mg/kg IP) from saline. Panels A and C include the cocaine dose-response function obtained for all rats (n=12). The dashed lines represent the thresholds for full (80%) and partial (20%) substitution. Asterisks (*p<0.05, **p<0.01) indicate significant differences compared to vehicle.