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Research ArticleNEUROPHARMACOLOGY

Modafinil Occupies Dopamine and Norepinephrine Transporters in Vivo and Modulates the Transporters and Trace Amine Activity in Vitro

Bertha K. Madras, Zhihua Xie, Zhicheng Lin, Amy Jassen, Helen Panas, Laurie Lynch, Ryan Johnson, Eli Livni, Thomas J. Spencer, Ali A. Bonab, Gregory M. Miller and Alan J. Fischman
Journal of Pharmacology and Experimental Therapeutics November 2006, 319 (2) 561-569; DOI: https://doi.org/10.1124/jpet.106.106583
Bertha K. Madras
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Zhihua Xie
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Zhicheng Lin
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Amy Jassen
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Helen Panas
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Laurie Lynch
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Ryan Johnson
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Eli Livni
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Thomas J. Spencer
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Ali A. Bonab
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Gregory M. Miller
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Alan J. Fischman
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Abstract

2-[(Diphenylmethyl) sulfinyl]acetamide (modafinil), prescribed principally to treat narcolepsy, is undergoing assessment for other neuropsychiatric disorders and medical conditions. The neurochemical substrates of modafinil are unresolved. We postulated that modafinil enhances wakefulness by modulating dopamine (DAT), norepinephrine (NET), or serotonin (SERT) transporter activities. In vivo, we determined DAT and NET occupancy by modafinil by positron emission tomography imaging; in vitro, we determined modafinil activity at the DAT, NET, SERT, and rhesus monkey trace amine receptor 1 (TA1). In rhesus monkey, modafinil occupancy of striatal DAT was detected by [11C]2β-carbomethoxy-3β-4-(fluorophenyl)tropane and of thalamic NET by [11C](S,S)-2-(α-(2-methoxyphenoxy)-benzyl)morpholine. In vitro, modafinil effects in DAT-human embryonic kidney (HEK), NET-HEK, and SERT-HEK cells were investigated alone or combined with the TA1 receptor. Modafinil (i.v.) occupied striatal DAT sites (5 mg/kg: 35 ± 12%, n = 4; 8 mg/kg: 54 ± 3%, n = 3). In thalamus, modafinil occupied NET sites (5 mg/kg: 16 ± 7.8%, n = 6; 8 mg/kg: 44 ± 12%; n = 2). In vitro, modafinil inhibited [3H]dopamine (IC50 = 6.4 μM), [3H]norepinephrine (IC50 = 35.6 μM), and [3H]serotonin (IC50 > 500 μM) transport via the human DAT, NET, and SERT. Modafinil did not activate the TA1 receptor in TA1-HEK cells, but it augmented a monoamine transporter-dependent enhancement of phenethylamine activation of TA1 in TA1-DAT and TA1-NET cells, but not in TA1-SERT cells. The present data provide compelling evidence that modafinil occupies the DAT and NET in living brain of rhesus monkeys and raise the possibility that modafinil affects wakefulness by interacting with catecholamine transporters in brain.

Footnotes

  • This study was supported by National Institutes of Health Grants DA11558 (to B.K.M.), DA06303 (to B.K.M.), DA15305 (to B.K.M.), DA16606 (to G.M.M.), and RR00168 (to NEPRC).

  • This study was reported in abstract form. Madras BK (2006) Modafinil potentiates trace amine receptor activity via the dopamine transporter in vitro and partially occupies the dopamine transporter in vivo, The Annual Meeting of the Society for Nuclear Medicine; 2006 Jun 3–7, San Diego, CA, Society for Nuclear Medicine, Reston, VA.

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

  • doi:10.1124/jpet.106.106583.

  • ABBREVIATIONS: DAT, dopamine transporter; NET, norepinephrine transporter; PET, positron emission tomography; CFT (WIN 35,428), 2β-carbomethoxy-3β-4-(fluorophenyl)tropane; MeNER, (S,S)-2-(α-(2-methoxyphenoxy)benzyl)morpholine; PEA, phenethylamine; TA1, trace amine receptor 1; HEK, human embryonic kidney; SERT, serotonin transporter; DA, dopamine; CRE, cAMP response element; RLU, relative light unit; TAR1, rhesus monkey trace amine receptor 1.

    • Received April 21, 2006.
    • Accepted July 26, 2006.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 384 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 384, Issue 2
1 Feb 2023
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Research ArticleNEUROPHARMACOLOGY

Modafinil Occupies Dopamine and Norepinephrine Transporters in Vivo and Modulates the Transporters and Trace Amine Activity in Vitro

Bertha K. Madras, Zhihua Xie, Zhicheng Lin, Amy Jassen, Helen Panas, Laurie Lynch, Ryan Johnson, Eli Livni, Thomas J. Spencer, Ali A. Bonab, Gregory M. Miller and Alan J. Fischman
Journal of Pharmacology and Experimental Therapeutics November 1, 2006, 319 (2) 561-569; DOI: https://doi.org/10.1124/jpet.106.106583

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Research ArticleNEUROPHARMACOLOGY

Modafinil Occupies Dopamine and Norepinephrine Transporters in Vivo and Modulates the Transporters and Trace Amine Activity in Vitro

Bertha K. Madras, Zhihua Xie, Zhicheng Lin, Amy Jassen, Helen Panas, Laurie Lynch, Ryan Johnson, Eli Livni, Thomas J. Spencer, Ali A. Bonab, Gregory M. Miller and Alan J. Fischman
Journal of Pharmacology and Experimental Therapeutics November 1, 2006, 319 (2) 561-569; DOI: https://doi.org/10.1124/jpet.106.106583
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