Elsevier

Biological Psychiatry

Volume 67, Issue 8, 15 April 2010, Pages 784-787
Biological Psychiatry

Brief Report
Action of Modafinil—Increased Motivation Via the Dopamine Transporter Inhibition and D1 Receptors?

https://doi.org/10.1016/j.biopsych.2009.12.015Get rights and content

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.

Section snippets

Animals

Dopamine D1R mice, from Jackson Laboratory (Bar Harbor, Maine), were backcrossed for 12 generations onto a C57BL/6J background. Male and female mice WT (n = 8), HT (n = 8), and KO (n = 5) were derived from heterozygous breeding pairs and genotyped. Procedures were approved by the University of California San Diego Institutional Animal Care and Use Committee.

Training and Testing

Training and testing took place in five-hole-operant-chambers (25 × 25 × 25 cm; Med Associates, St. Albans, Vermont). Mice were shaped to

Training

Results are detailed in Supplement 1. The WT and HT mice readily trained to an FR1 and did not differ in total responses [F(1,130) < 1], whereas KO mice did not respond to an FR1, consistent with previous reports (12), and therefore experimental challenge results were compared only between WT and HT mice. No effects of gender or drug × gender interactions were found (p > .1).

Experiment 1: Modafinil Effects on Motivation and Speed of Performance

Main effects of drug [F(3,45) = 4.3, p < .05] and gene [F(1,15) = 5.2, p < .05] and a trend toward a drug × gene

Discussion

Modafinil increased motivation and sped the performance of dopamine D1R WT and HT mice in a PRBS. The effects of modafinil were consistent with those of the selective DAT inhibitor GBR12909. The drug × gene interactions observed for these two compounds suggest that the drug-induced increases in motivation were more robust in WT compared with HT mice. No effect was observed in D1R KO mice, due to their lack of operant responding for reward. The data indicate several important aspects regarding

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