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Molecular Pharmacology

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Research ArticleArticle

Relationship between Conformational Changes in the Dopamine Transporter and Cocaine-Like Subjective Effects of Uptake Inhibitors

Claus J. Loland, Rajeev I. Desai, Mu-Fa Zou, Jianjing Cao, Peter Grundt, Klaus Gerstbrein, Harald H. Sitte, Amy Hauck Newman, Jonathan L. Katz and Ulrik Gether
Molecular Pharmacology March 2008, 73 (3) 813-823; DOI: https://doi.org/10.1124/mol.107.039800
Claus J. Loland
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Rajeev I. Desai
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Mu-Fa Zou
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Jianjing Cao
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Peter Grundt
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Klaus Gerstbrein
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Harald H. Sitte
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Amy Hauck Newman
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Jonathan L. Katz
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Ulrik Gether
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Abstract

Cocaine exerts its stimulatory effect by inhibiting the dopamine transporter (DAT). However, novel benztropine- and rimcazole-based inhibitors show reduced stimulant effects compared with cocaine, despite higher affinity and selectivity for DAT. To investigate possible mechanisms, we compared the subjective effects of different inhibitors with their molecular mode of interaction at the DAT. We determined how different inhibitors affected accessibility of the sulfhydryl-reactive reagent [2-(trimethylammonium)ethyl]-methanethiosulfonate to an inserted cysteine (I159C), which is accessible when the extracellular transporter gate is open but inaccessible when it is closed. The data indicated that cocaine analogs bind an open conformation, whereas benztropine and rimcazole analogs bind a closed conformation. Next, we investigated the changes in inhibition potency of [3H]dopamine uptake of the compounds at a mutant DAT (Y335A) characterized by a global change in the conformational equilibrium. We observed a close relationship between the decrease in potencies of inhibitors at this mutant and cocaine-like responding in rats trained to discriminate cocaine from saline injections. Our data suggest that chemically different DAT inhibitors stabilize distinct transporter conformations and that this in turn affects the cocaine-like subjective effects of these compounds in vivo.

Footnotes

  • The work was supported in part by funds from the Lundbeck Foundation (to C.J.L. and U.G.), the Danish Health Science Research Council (to C.J.L. and U.G.), National Institute of Health Grant P01 DA-12408 (to U.G.), the Novo Nordic Foundation (to C.J.L. and U.G.), the Maersk Foundation (to C.J.L.), the National Institute on Drug Abuse Intramural Research Program (to J.K. and A.H.N.), and Austrian Science Foundation/Fonds zur Förderung der wissen-schaftlichen Forschung Grant P17076 (to H.H.S.).

  • ABBREVIATIONS: DAT, dopamine transporter; BZT, benztropine; TM, transmembrane domain; WIN 35,428, 2β-carbomethoxy-3β-(4-fluorophenyl)tropane; RTI-55, 2β-carbomethoxy-3β-(4-iodophenyl)tropane; AHN 1-055, 3α-[bis-(4-fluorophenyl)methoxy]tropane; AHN 2-005, N-allyl-3α-[bis-(4-fluorophenyl)methoxy]tropane; RT, room temperature; MTSET, [2-(trimethylammonium)ethyl]-methanethiosulfonate; FR, fixed ratio; ANOVA, analysis of variance; LeuT, leucine transporter; WT, wild type; NET, norepinephrine transporter; SERT, serotonin transporter; Ro 41-0960, 2′-fluoro-3,4-dihydroxy-5-nitrobenzophenone.

    • Received July 13, 2007.
    • Accepted October 31, 2007.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 73 (3)
Molecular Pharmacology
Vol. 73, Issue 3
1 Mar 2008
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Research ArticleArticle

Relationship between Conformational Changes in the Dopamine Transporter and Cocaine-Like Subjective Effects of Uptake Inhibitors

Claus J. Loland, Rajeev I. Desai, Mu-Fa Zou, Jianjing Cao, Peter Grundt, Klaus Gerstbrein, Harald H. Sitte, Amy Hauck Newman, Jonathan L. Katz and Ulrik Gether
Molecular Pharmacology March 1, 2008, 73 (3) 813-823; DOI: https://doi.org/10.1124/mol.107.039800

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Research ArticleArticle

Relationship between Conformational Changes in the Dopamine Transporter and Cocaine-Like Subjective Effects of Uptake Inhibitors

Claus J. Loland, Rajeev I. Desai, Mu-Fa Zou, Jianjing Cao, Peter Grundt, Klaus Gerstbrein, Harald H. Sitte, Amy Hauck Newman, Jonathan L. Katz and Ulrik Gether
Molecular Pharmacology March 1, 2008, 73 (3) 813-823; DOI: https://doi.org/10.1124/mol.107.039800
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