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Research ArticleBehavioral Pharmacology

Blockade of Cocaine or σ Receptor Agonist Self Administration by Subtype-Selective σ Receptor Antagonists

Jonathan L. Katz, Takato Hiranita, Theresa A. Kopajtic, Kenner C. Rice, Christophe Mesangeau, Sanju Narayanan, Ahmed H. Abdelazeem and Christopher R. McCurdy
Journal of Pharmacology and Experimental Therapeutics July 2016, 358 (1) 109-124; DOI: https://doi.org/10.1124/jpet.116.232728
Jonathan L. Katz
Psychobiology Section, Intramural Research Program, National Institutes of Health National Institute on Drug Abuse, Baltimore, Maryland (J.L.K., T.H., T.A.K.); Drug Design and Synthesis Section, Intramural Research Program, National Institutes of Health National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism, Baltimore, Maryland (K.C.R.); and Department of BioMolecular Sciences, School of Pharmacy, University of Mississippi, University, Mississippi (C.M., S.N., A.H.A., C.R.M.)
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Takato Hiranita
Psychobiology Section, Intramural Research Program, National Institutes of Health National Institute on Drug Abuse, Baltimore, Maryland (J.L.K., T.H., T.A.K.); Drug Design and Synthesis Section, Intramural Research Program, National Institutes of Health National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism, Baltimore, Maryland (K.C.R.); and Department of BioMolecular Sciences, School of Pharmacy, University of Mississippi, University, Mississippi (C.M., S.N., A.H.A., C.R.M.)
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Theresa A. Kopajtic
Psychobiology Section, Intramural Research Program, National Institutes of Health National Institute on Drug Abuse, Baltimore, Maryland (J.L.K., T.H., T.A.K.); Drug Design and Synthesis Section, Intramural Research Program, National Institutes of Health National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism, Baltimore, Maryland (K.C.R.); and Department of BioMolecular Sciences, School of Pharmacy, University of Mississippi, University, Mississippi (C.M., S.N., A.H.A., C.R.M.)
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Kenner C. Rice
Psychobiology Section, Intramural Research Program, National Institutes of Health National Institute on Drug Abuse, Baltimore, Maryland (J.L.K., T.H., T.A.K.); Drug Design and Synthesis Section, Intramural Research Program, National Institutes of Health National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism, Baltimore, Maryland (K.C.R.); and Department of BioMolecular Sciences, School of Pharmacy, University of Mississippi, University, Mississippi (C.M., S.N., A.H.A., C.R.M.)
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Christophe Mesangeau
Psychobiology Section, Intramural Research Program, National Institutes of Health National Institute on Drug Abuse, Baltimore, Maryland (J.L.K., T.H., T.A.K.); Drug Design and Synthesis Section, Intramural Research Program, National Institutes of Health National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism, Baltimore, Maryland (K.C.R.); and Department of BioMolecular Sciences, School of Pharmacy, University of Mississippi, University, Mississippi (C.M., S.N., A.H.A., C.R.M.)
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Sanju Narayanan
Psychobiology Section, Intramural Research Program, National Institutes of Health National Institute on Drug Abuse, Baltimore, Maryland (J.L.K., T.H., T.A.K.); Drug Design and Synthesis Section, Intramural Research Program, National Institutes of Health National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism, Baltimore, Maryland (K.C.R.); and Department of BioMolecular Sciences, School of Pharmacy, University of Mississippi, University, Mississippi (C.M., S.N., A.H.A., C.R.M.)
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Ahmed H. Abdelazeem
Psychobiology Section, Intramural Research Program, National Institutes of Health National Institute on Drug Abuse, Baltimore, Maryland (J.L.K., T.H., T.A.K.); Drug Design and Synthesis Section, Intramural Research Program, National Institutes of Health National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism, Baltimore, Maryland (K.C.R.); and Department of BioMolecular Sciences, School of Pharmacy, University of Mississippi, University, Mississippi (C.M., S.N., A.H.A., C.R.M.)
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Christopher R. McCurdy
Psychobiology Section, Intramural Research Program, National Institutes of Health National Institute on Drug Abuse, Baltimore, Maryland (J.L.K., T.H., T.A.K.); Drug Design and Synthesis Section, Intramural Research Program, National Institutes of Health National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism, Baltimore, Maryland (K.C.R.); and Department of BioMolecular Sciences, School of Pharmacy, University of Mississippi, University, Mississippi (C.M., S.N., A.H.A., C.R.M.)
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Abstract

The identification of sigma receptor (σR) subtypes has been based on radioligand binding and, despite progress with σ1R cellular function, less is known about σR subtype functions in vivo. Recent findings that cocaine self administration experience will trigger σR agonist self administration was used in this study to assess the in vivo receptor subtype specificity of the agonists (+)-pentazocine, PRE-084 [2-(4-morpholinethyl) 1-phenylcyclohexanecarboxylate hydrochloride], and 1,3-di-o-tolylguanidine (DTG) and several novel putative σR antagonists. Radioligand binding studies determined in vitro σR selectivity of the novel compounds, which were subsequently studied for self administration and antagonism of cocaine, (+)-pentazocine, PRE-084, or DTG self administration. Across the dose ranges studied, none of the novel compounds were self administered, nor did they alter cocaine self administration. All compounds blocked DTG self administration, with a subset also blocking (+)-pentazocine and PRE-084 self administration. The most selective of the compounds in binding σ1Rs blocked cocaine self administration when combined with a dopamine transport inhibitor, either methylphenidate or nomifensine. These drug combinations did not decrease rates of responding maintained by food reinforcement. In contrast, the most selective of the compounds in binding σ2Rs had no effect on cocaine self administration in combination with either dopamine transport inhibitor. Thus, these results identify subtype-specific in vivo antagonists, and the utility of σR agonist substitution for cocaine self administration as an assay capable of distinguishing σR subtype selectivity in vivo. These results further suggest that effectiveness of dual σR antagonism and dopamine transport inhibition in blocking cocaine self administration is specific for σ1Rs and further support this dual targeting approach to development of cocaine antagonists.

Footnotes

    • Received February 4, 2016.
    • Accepted April 14, 2016.
  • ↵1 Current affiliation: Division of Neurotoxicology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, Arkansas.

  • This research was supported by the National Institutes of Health National Institute on Drug Abuse [Grant R01-DA023205 (to C.R.M.)] and the National Institutes of Health National Institute of General Medical Sciences [Grant P20-GM104932 (to C.R.M.)]. This research was supported [in part] by the Intramural Research Program of the National Institutes of Health National Institute on Drug Abuse and the National Institute on Alcohol Abuse and Alcoholism.

  • Some of the data reported herein were presented at the following meetings: Hiranita T, Mereu M, Tanda G, Kopajtic TA, Mesangeau C, McCurdy CR and Katz JL (2012) Combined dopamine transporter and σ receptor actions: effects of σ receptor subtype. Annual Meeting at Society for Neuroscience; 2012 Oct 13-17; New Orleans, LA. Katz JL, McCurdy CR, and Hiranita T (2013) Validation of σ-Receptor Agonist Self Administration as a Method for in vivo Characterization of σ-Receptor Agonist or Antagonist Activity. 56th Annual Meeting at Behavioral Pharmacology Society; 2013 Apr 20-24; Boston, MA.

  • dx.doi.org/10.1124/jpet.116.232728.

  • U.S. Government work not protected by U.S. copyright
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Journal of Pharmacology and Experimental Therapeutics: 358 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 358, Issue 1
1 Jul 2016
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Research ArticleBehavioral Pharmacology

Subtype-Selective σ Antagonists and Self Administration

Jonathan L. Katz, Takato Hiranita, Theresa A. Kopajtic, Kenner C. Rice, Christophe Mesangeau, Sanju Narayanan, Ahmed H. Abdelazeem and Christopher R. McCurdy
Journal of Pharmacology and Experimental Therapeutics July 1, 2016, 358 (1) 109-124; DOI: https://doi.org/10.1124/jpet.116.232728

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Research ArticleBehavioral Pharmacology

Subtype-Selective σ Antagonists and Self Administration

Jonathan L. Katz, Takato Hiranita, Theresa A. Kopajtic, Kenner C. Rice, Christophe Mesangeau, Sanju Narayanan, Ahmed H. Abdelazeem and Christopher R. McCurdy
Journal of Pharmacology and Experimental Therapeutics July 1, 2016, 358 (1) 109-124; DOI: https://doi.org/10.1124/jpet.116.232728
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