Abstract
Modafinil is prescribed for numerous medical conditions, but the drug's mechanism of action is unclear. Here, we examined the interaction of modafinil with receptors and transporters in vitro and compared pharmacological effects of the drug with those produced by indirect dopamine (DA) agonists 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine (GBR12909) and (+)-methamphetamine (METH). Modafinil was screened at various receptors and transporters using binding assays. Transporter-mediated uptake and release were examined in rat brain synaptosomes. Effects of modafinil on motor activity and neurochemistry were determined in rats undergoing in vivo microdialysis in nucleus accumbens. Of the receptors and transporters assayed, modafinil displayed measurable potency only at DA transporters (DAT), inhibiting [3H]DA uptake, with an IC50 value of 4.0 μM. Accordingly, modafinil pretreatment (10 μM) antagonized METH-induced release of the DAT substrate [3H]1-methyl-4-phenylpyridinium. Intravenous modafinil (20 and 60 mg/kg) produced dose-dependent increases in motor activity and extracellular DA, without affecting serotonin (5-HT). Analogous results were observed for GBR12909 (1 and 3 mg/kg), whereas METH (0.3 and 1 mg/kg) increased DA and 5-HT. Locomotor effects of all drugs were positively correlated with dialysate DA (P < 0.001). Interestingly, modafinil pretreatment reduced METH-induced ambulation and DA release. Our data show that modafinil interacts with DAT sites in rat brain, a property shared with agonist medications under investigation for treating cocaine dependence. Nondopaminergic mechanisms may also contribute to the pharmacology of modafinil. Finally, the results suggest that modafinil should be tested as an adjunct for treating METH addiction.
Footnotes
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This research was supported in part by the Intramural Research Program of the National Institutes of Health National Institute on Drug Abuse.
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R.J. is supported by the National Institutes of Health National Institute on Drug Abuse Distinguished International Scientist Collaboration Award Program.
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This work was presented previously. Baumann MH, Zolkowska D, Jain R, Partilla JS, Prisinzano TE, and Rothman RB (2008) Evidence that stimulant effects of modafinil in rats involve dopamine transporters. College on Problems of Drug Dependence, 70th Annual Scientific Meeting; 2008 June 18; San Juan, P.R. College on Problems of Drug Dependence, Philadelphia, PA.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.108.146142.
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ABBREVIATIONS: DA, dopamine; 5-HT, 5-hydroxytryptamine (serotonin); DAT, dopamine transporter(s); NE, norepinephrine; NET, norepinephrine transporter(s); GBR12935, 1-[2-benzhydroxyethyl]-4-(3-phenylpropyl)piperazine; METH, (+)-methamphetamine; RTI-55, 3β-(4-iodophenyl)-tropan-2β-carboxylic acid methyl ester; SERT, serotonin transporter(s); MPP+, 1-methyl-4-phenylpyridinium; HPLC-ECD, high-pressure liquid chromatography with electrochemical detection; ANOVA, analysis of variance; MeNER, (S,S)-2-(α-(2-methoxyphenoxy)benzyl)morpholine; n., nucleus; SCH23390, R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine; GR125743, N-[4-methoxy-3-(4-methyl piperazin-1-yl)phenyl]-3-methyl-4-(4-pyridyl)benzamide; MK-801, 5H-dibenzo[a,d]cyclohepten-5,10-imine (dizocilpine maleate); [125I]HEAT, [125I]iodo-2-[β-(4-hydroxyphenyl)-ethylaminomethyl]tetralone; [3H]N-methylspiperone.
- Received September 15, 2008.
- Accepted January 26, 2009.
- U.S. Government work not protected by U.S. copyright
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