title: Blockade of Cocaine or σ Receptor Agonist Self Administration by Subtype-Selective σ Receptor Antagonists.
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.
authors.affiliation: 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.) jkatz@intra.nida.nih.gov.
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Katz
authors.affiliation: 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.).
authors.forename: Takato
authors.initials: T
authors.lastname: Hiranita
authors.affiliation: 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.).
authors.forename: Theresa A
authors.initials: TA
authors.lastname: Kopajtic
authors.affiliation: 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.).
authors.forename: Kenner C
authors.initials: KC
authors.lastname: Rice
authors.affiliation: 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.).
authors.forename: Christophe
authors.initials: C
authors.lastname: Mesangeau
authors.affiliation: 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.).
authors.forename: Sanju
authors.initials: S
authors.lastname: Narayanan
authors.affiliation: 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.).
authors.forename: Ahmed H
authors.initials: AH
authors.lastname: Abdelazeem
authors.affiliation: 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.).
authors.forename: Christopher R
authors.initials: CR
authors.lastname: McCurdy
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D003042:Cocaine / Q000008:administration & dosage / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006146:Guanidines / Q000008:administration & dosage / Q000494:pharmacology; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008024:Ligands; D008297:Male; D009025:Morpholines / Q000008:administration & dosage / Q000494:pharmacology; D010423:Pentazocine / Q000008:administration & dosage / Q000494:pharmacology; D011485:Protein Binding; D011869:Radioligand Assay; D017207:Rats, Sprague-Dawley; D017480:Receptors, sigma / Q000819:agonists / Q000037:antagonists & inhibitors; D012646:Self Administration
chemical_list: D006146:Guanidines; D008024:Ligands; D009025:Morpholines; D017480:Receptors, sigma; C071738:2-(4-morpholino)ethyl-1-phenylcyclohexane-1-carboxylate; D003042:Cocaine; C050232:1,3-ditolylguanidine; D010423:Pentazocine