Modafinil evokes striatal [ 3 H]dopamine release and alters the subjective properties of stimulants Marsha M. Dopheide a,b , Russell E. Morgan c , Kelli R. Rodvelt a , Todd R. Schachtman a,d , Dennis K. Miller a,d, ⁎ a Department of Psychological Sciences, University of Missouri, Columbia MO, USA b Department of Psychology, Monmouth College, Monmouth IL, USA c Department of Psychology, Western Illinois University, Macomb IL, USA d Interdisciplinary Neuroscience Program, University of Missouri, Columbia MO, USA Received 13 October 2006; received in revised form 23 March 2007; accepted 26 March 2007 Available online 5 April 2007 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 μM) 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 μM) blocked modafinil-evoked [ 3 H]overflow, and concentrations of modafinil (b 100 μM) that did not have intrinsic activity attenuated amphetamine (1 and 3 μM)-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. © 2007 Elsevier B.V. All rights reserved. Keywords: Amphetamine; Cocaine; Dopamine; Modafinil; Nicotine; Nicotinic acetylcholine receptor 1. Introduction Modafinil (diphenyl-methyl sulphinil-2-acetamide; Provigil, Alertec and Vigiler) is a wake-promoting psychostimulant that is approved by the U.S. Food and Drug Administration for the treatment of narcolepsy, shift work sleep disorder and as an adjunctive treatment for obstructive sleep apnea/hypopnea syndrome (Ballon and Feifel, 2006). Modafinil also is effective for attenuating the symptoms of Attention-Deficit Hyperactivity Disorder, symptoms of dysphoric mood disorders, negative symptoms of schizophrenia, and cognitive deficits found in organic brain syndromes and Alzheimer's Disease (Nasr, 2004; Ballon and Feifel, 2006; Krebs et al., 2006). A concern with the use of traditional psychostimulants, such as amphetamines, for psychiatric disorders is their relatively-high abuse and dependence liability. However, research in humans suggests that modafinil has less of an abuse liability than amphetamines or cocaine (Warot et al., 1993; Jasinski and Kovacevic-Ristanovic, 2000; Myrick et al., 2004). In a drug discrimination assay, modafinil induced a state that was distinct from amphetamine and cocaine (Warot et al., 1993; Rush et al., 2002). Moreover, modafinil has recently been considered as a treatment to minimize the withdrawal symptoms from long-term amphetamine or cocaine use (Dackis et al., 2003, 2005). European Journal of Pharmacology 568 (2007) 112 – 123 www.elsevier.com/locate/ejphar ⁎ Corresponding author. Department of Psychological Sciences, University of Missouri, 212-C McAlester Hall, Columbia MO 65202, USA. Tel.: +1 573 884 8141; fax: +1 573 882 7710. E-mail address: millerden@missouri.edu (D.K. Miller). 0014-2999/$ - see front matter © 2007 Elsevier B.V. All rights reserved. doi:10.1016/j.ejphar.2007.03.044