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

ABSTRACT: 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.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.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.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.

SUBMITTER: Young JW

PROVIDER: S-EPMC2849918 | biostudies-literature | 2010 Apr

REPOSITORIES: biostudies-literature

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

Young Jared W JW Geyer Mark A MA

Biological psychiatry 20100204 8

<h4>Background</h4>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.<h4>Methods</h4>Dopamine D1R wildtype (WT), heter ...[more]

PMID: 20132929

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Project description:A rat model of diet-induced obesity (DIO) was used to determine dopamine transporter (DAT) function, impulsivity and motivation as neurobehavioral outcomes and predictors of obesity.To evaluate neurobehavioral alterations following the development of DIO induced by an 8-week high-fat diet (HF) exposure, striatal D2-receptor density, DAT function and expression, extracellular dopamine concentrations, impulsivity, and motivation for high- and low-fat reinforcers were determined. To determine predictors of DIO, neurobehavioral antecedents including impulsivity, motivation for high-fat reinforcers, DAT function and extracellular dopamine were evaluated before the 8-week HF exposure.Striatal D2-receptor density was determined by in vitro kinetic analysis of [(3)H]raclopride binding. DAT function was determined using in vitro kinetic analysis of [(3)H]dopamine uptake, methamphetamine-evoked [(3)H]dopamine overflow and no-net flux in vivo microdialysis. DAT cell-surface expression was determined using biotinylation and western blotting. Impulsivity and food-motivated behavior were determined using a delay discounting task and progressive ratio schedule, respectively.Relative to obesity-resistant (OR) rats, obesity-prone (OP) rats exhibited 18% greater body weight following an 8-week HF-diet exposure, 42% lower striatal D2-receptor density, 30% lower total DAT expression, 40% lower in vitro and in vivo DAT function, 45% greater extracellular dopamine and twofold greater methamphetamine-evoked [(3)H]dopamine overflow. OP rats exhibited higher motivation for food, and surprisingly, were less impulsive relative to OR rats. Impulsivity, in vivo DAT function and extracellular dopamine concentration did not predict DIO. Importantly, motivation for high-fat reinforcers predicted the development of DIO.Human studies are limited by their ability to determine if impulsivity, motivation and DAT function are causes or consequences of DIO. The current animal model shows that motivation for high-fat food, but not impulsive behavior, predicts the development of obesity, whereas decreases in striatal DAT function are exhibited only after the development of obesity.

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

Publications

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

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