Action of modafinil--increased motivation via the dopamine transporter inhibition and D1 receptors?

Abstract

Background: Modafinil is prescribed for the treatment of narcolepsy. It has been postulated that modafinil might treat cognitive disruption in neuropsychiatric disorders. The mechanisms underlying such modafinil-induced improvements in performance have yet to be delineated however. Recent evidence suggests that modafinil might block the dopamine transporter (DAT) and that the dopamine D1 receptor (D1R) might contribute to modafinil effects.

Methods: Dopamine D1R wildtype (WT), heterozygous (HT), and knockout (KO) mice received vehicle, modafinil, or the selective DAT blocker GBR12909 in a progressive ratio breakpoint study.

Results: Both modafinil and GBR12909 increased motivation in the task as measured by an increase in breakpoint in WT and HT mice. These drug-induced increases in motivation were reduced in dopamine D1R HT mice relative to their WT littermates. The D1R KO mice did not respond in the task.

Conclusions: These data support the hypothesis that modafinil increases motivation. Moreover, given the similarity of effects with GBR12909, the data corroborate evidence that the behavioral effects of modafinil might be due to DAT inhibition. Furthermore, the dopamine D1R might play a downstream role in mediating modafinil-induced increases in motivation. Thus, studies reporting cognition-enhancing effects of modafinil might have been influenced by its ability to increase motivation.

Figure 1. Modafinil-induced increase in motivation and speeding of performance

Modafinil increased breakpoint in D1R WT and HT mice, with lower doses being needed for WT mice (A). Due to a lack of response, KO mice were not included in the analyses. Modafinil lowered response (B) and reward latencies (C) irrespective of genotype. Data presented as mean + s.e.m. * denotes p<0.05 compared to vehicle dose.

Figure 2. GBR12909-induced increase in motivation and speeding of performance

GBR 12909 significantly increased breakpoint in D1R WT and HT mice, with greater effects observed in WT mice (A). Due to a lack of response, KO mice were not included in the analyses. GBR 12909 also sped performance at the lowest dose as measured by response (B) and reward latencies (C), irrespective of genotype. Data presented as mean + s.e.m. * denotes p<0.05 compared to vehicle dose, $ denotes p<0.08 compared to HT mice.