Dopaminergic mediation of the discriminative stimulus functions of modafinil in rats

Psychopharmacology (Berl). 2015 Dec;232(24):4411-9. doi: 10.1007/s00213-015-4065-0. Epub 2015 Sep 15.


Rationale: Modafinil is a wake-promoting drug with FDA approval for the treatment of excessive daytime sleepiness that has been prescribed for ADHD and recently assessed as a potential treatment for psychostimulant dependence. Previous research indicates that modafinil modestly increases locomotor activity and produces similar discriminative stimulus effects to psychostimulants in rodents, although the subjective effects of modafinil are reportedly distinct from those of cocaine or amphetamine in humans with a history of psychostimulant abuse.

Objectives: The current study employed drug discrimination procedures in rats to examine the pharmacological actions contributing to modafinil's discriminative stimulus functions.

Methods: Eight male Sprague-Dawley rats were trained to discriminate intragastric administration of 256 mg/kg modafinil from vehicle (5% arabic gum) under a FR 20 schedule of food reinforcement. Substitution tests were conducted with various dopaminergic agents (d-amphetamine, cocaine, PNU-91356A, GBR 12909, methylphenidate) and nondopaminergic agents (nicotine, ethanol). Antagonist tests were conducted with the selective D1 antagonist, SCH 39166, and the nonselective D2 antagonist, haloperidol.

Results: Rats trained to discriminate modafinil displayed complete stimulus generalization to cocaine, methylphenidate, and GBR 12909 and the discrimination was completely blocked by both SCH 39166 and haloperidol. Evidence for significant partial substitution was obtained with d-amphetamine, PNU-91356A, and nicotine.

Conclusions: Results strongly support the role of dopaminergic mechanisms in the discriminative stimulus functions of modafinil, although further evaluation regarding the contribution of other neurotransmitter systems to these effects should be continued. The findings are discussed in light of clinical research efforts with modafinil as a treatment for psychostimulant dependence.

Keywords: Amphetamine; Cocaine; Drug discrimination; GBR 12909; Methylphenidate; Modafinil; Rats.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Amphetamine / pharmacology
  • Animals
  • Benzhydryl Compounds / pharmacology*
  • Central Nervous System Stimulants / pharmacology
  • Cocaine / pharmacology
  • Dextroamphetamine / pharmacology
  • Dopamine / physiology*
  • Dopamine Agents / pharmacology*
  • Generalization, Psychological / drug effects*
  • Male
  • Methylphenidate / pharmacology
  • Modafinil
  • Nicotine / pharmacology
  • Piperazines / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Reinforcement, Psychology
  • Wakefulness-Promoting Agents / pharmacology*


  • (1-(2-(bis(4-fluorophenyl)methoxy)ethyl)-4-(3-hydroxy-3-phenylpropyl) piperazinyl decanoate)
  • Benzhydryl Compounds
  • Central Nervous System Stimulants
  • Dopamine Agents
  • Piperazines
  • Wakefulness-Promoting Agents
  • Methylphenidate
  • Nicotine
  • Amphetamine
  • Cocaine
  • Modafinil
  • Dextroamphetamine
  • Dopamine