Modafinil evokes striatal [(3)H]dopamine release and alters the subjective properties of stimulants.

Abstract

Modafinil is a mild psychostimulant used for the treatment of sleep and arousal-related disorders, and has been considered a pharmacotherapy for cocaine and amphetamine dependence; however, modafinil's mechanism of action is largely unclear. The present study investigated modafinil using drug discrimination and slice superfusion techniques. Rats were trained to discriminate cocaine (1.6 or 5 mg/kg) or amphetamine (0.3 mg/kg) from saline injection for food reinforcement. Modafinil (64-128 mg/kg) substituted partially for both cocaine doses and amphetamine. Pretreatment with a lower modafinil dose (32 mg/kg) augmented the discriminative stimulus properties of cocaine (1.6 mg/kg dose group) and amphetamine. In neurochemical experiments, modafinil (100-300 microM) evoked [(3)H]overflow from rat striatal slices preloaded with [(3)H]dopamine in a concentration-dependent manner; however, modafinil was less potent and efficacious than amphetamine and nicotine. The dopamine transporter inhibitor nomifensine (10 microM) blocked modafinil-evoked [(3)H]overflow, and concentrations of modafinil (<100 microM) that did not have intrinsic activity attenuated amphetamine (1 and 3 microM)-evoked [(3)H]overflow. Modafinil-evoked [(3)H]overflow was not altered by the nicotinic acetylcholine receptor antagonist mecamylamine, and modafinil did not alter nicotine-evoked [(3)H]overflow, indicating that nicotinic acetylcholine receptors likely are not important for modafinil's mechanism of action. The present results indicate that modafinil evokes dopamine release from striatal neurons and is a psychostimulant that is pharmacologically similar to, but much less potent and efficacious than, amphetamine.

• Authors: Marsha M Dopheide, Russell E Morgan, Kelli R Rodvelt, Todd R Schachtman, Dennis K Miller
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 568 Issue 1-3 Pg. 112-23 (Jul 30 2007) ISSN: 0014-2999 [Print] Netherlands
• PMID: 17477916 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Benzhydryl Compounds
• Central Nervous System Stimulants
• Dopamine Uptake Inhibitors
• Nomifensine
• Nicotine
• Amphetamine
• Cocaine
• Modafinil
• Dopamine

Topics

• Amphetamine (pharmacology)
• Animals
• Benzhydryl Compounds (pharmacology)
• Central Nervous System Stimulants (pharmacology)
• Cocaine (pharmacology)
• Corpus Striatum (drug effects, metabolism)
• Dopamine (metabolism)
• Dopamine Uptake Inhibitors (pharmacology)
• Male
• Modafinil
• Nicotine (pharmacology)
• Nomifensine (pharmacology)
• Rats
• Rats, Sprague-Dawley