title: Relationship between cerebral sigma-1 receptor occupancy and attenuation of cocaine's motor stimulatory effects in mice by PD144418.
abstract: Psychostimulant effects of cocaine are mediated partly by agonist actions at sigma-1 (σ1) receptors. Selective σ1 receptor antagonists attenuate these effects and provide a potential avenue for pharmacotherapy. However, the selective and high affinity σ1 antagonist PD144418 (1,2,3,6-tetrahydro-5-[3-(4-methylphenyl)-5-isoxazolyl]-1-propylpyridine) has been reported not to inhibit cocaine-induced hyperactivity. To address this apparent paradox, we evaluated aspects of PD144418 binding in vitro, investigated σ1 receptor and dopamine transporter (DAT) occupancy in vivo, and re-examined effects on locomotor activity. PD144418 displayed high affinity for σ1 sites (Ki 0.46 nM) and 3596-fold selectivity over σ2 sites (Ki 1654 nM) in guinea pig brain membranes. No appreciable affinity was noted for serotonin and norepinephrine transporters (Ki >100 μM), and the DAT interaction was weak (Ki 9.0 μM). In vivo, PD144418 bound to central and peripheral σ1 sites in mouse, with an ED50 of 0.22 μmol/kg in whole brain. No DAT occupancy by PD144418 (10.0 μmol/kg) or possible metabolites were observed. At doses that did not affect basal locomotor activity, PD144418 (1, 3.16, and 10 μmol/kg) attenuated cocaine-induced hyperactivity in a dose-dependent manner in mice. There was good correlation (r(2) = 0.88) of hyperactivity reduction with increasing cerebral σ1 receptor occupancy. The behavioral ED50 of 0.79 μmol/kg corresponded to 80% occupancy. Significant σ1 receptor occupancy and the ability to mitigate cocaine's motor stimulatory effects were observed for 16 hours after a single 10.0 μmol/kg dose of PD144418.
authors.affiliation: Research Service, Harry S. Truman Memorial Veterans' Hospital, Columbia, Missouri (J.R.L., E.A.F.-C., L.D.W., T.L.C.); and Department of Radiology and Radiopharmaceutical Sciences Institute (J.R.L., E.A.F.-C., L.D.W., T.L.C.), Department of Medical Pharmacology and Physiology (J.R.L.), Department of Psychological Sciences (D.K.M., C.L.G.), Center for Translational Neuroscience (D.K.M.), Department of Chemistry (S.Z.L.), and MU Research Reactor Center (S.Z.L.), University of Missouri, Columbia, Missouri leverj@health.missouri.edu.
authors.forename: John R
authors.initials: JR
authors.lastname: Lever
authors.affiliation: Research Service, Harry S. Truman Memorial Veterans' Hospital, Columbia, Missouri (J.R.L., E.A.F.-C., L.D.W., T.L.C.); and Department of Radiology and Radiopharmaceutical Sciences Institute (J.R.L., E.A.F.-C., L.D.W., T.L.C.), Department of Medical Pharmacology and Physiology (J.R.L.), Department of Psychological Sciences (D.K.M., C.L.G.), Center for Translational Neuroscience (D.K.M.), Department of Chemistry (S.Z.L.), and MU Research Reactor Center (S.Z.L.), University of Missouri, Columbia, Missouri.
authors.forename: Dennis K
authors.initials: DK
authors.lastname: Miller
authors.affiliation: Research Service, Harry S. Truman Memorial Veterans' Hospital, Columbia, Missouri (J.R.L., E.A.F.-C., L.D.W., T.L.C.); and Department of Radiology and Radiopharmaceutical Sciences Institute (J.R.L., E.A.F.-C., L.D.W., T.L.C.), Department of Medical Pharmacology and Physiology (J.R.L.), Department of Psychological Sciences (D.K.M., C.L.G.), Center for Translational Neuroscience (D.K.M.), Department of Chemistry (S.Z.L.), and MU Research Reactor Center (S.Z.L.), University of Missouri, Columbia, Missouri.
authors.forename: Emily A
authors.initials: EA
authors.lastname: Fergason-Cantrell
authors.affiliation: Research Service, Harry S. Truman Memorial Veterans' Hospital, Columbia, Missouri (J.R.L., E.A.F.-C., L.D.W., T.L.C.); and Department of Radiology and Radiopharmaceutical Sciences Institute (J.R.L., E.A.F.-C., L.D.W., T.L.C.), Department of Medical Pharmacology and Physiology (J.R.L.), Department of Psychological Sciences (D.K.M., C.L.G.), Center for Translational Neuroscience (D.K.M.), Department of Chemistry (S.Z.L.), and MU Research Reactor Center (S.Z.L.), University of Missouri, Columbia, Missouri.
authors.forename: Caroline L
authors.initials: CL
authors.lastname: Green
authors.affiliation: Research Service, Harry S. Truman Memorial Veterans' Hospital, Columbia, Missouri (J.R.L., E.A.F.-C., L.D.W., T.L.C.); and Department of Radiology and Radiopharmaceutical Sciences Institute (J.R.L., E.A.F.-C., L.D.W., T.L.C.), Department of Medical Pharmacology and Physiology (J.R.L.), Department of Psychological Sciences (D.K.M., C.L.G.), Center for Translational Neuroscience (D.K.M.), Department of Chemistry (S.Z.L.), and MU Research Reactor Center (S.Z.L.), University of Missouri, Columbia, Missouri.
authors.forename: Lisa D
authors.initials: LD
authors.lastname: Watkinson
authors.affiliation: Research Service, Harry S. Truman Memorial Veterans' Hospital, Columbia, Missouri (J.R.L., E.A.F.-C., L.D.W., T.L.C.); and Department of Radiology and Radiopharmaceutical Sciences Institute (J.R.L., E.A.F.-C., L.D.W., T.L.C.), Department of Medical Pharmacology and Physiology (J.R.L.), Department of Psychological Sciences (D.K.M., C.L.G.), Center for Translational Neuroscience (D.K.M.), Department of Chemistry (S.Z.L.), and MU Research Reactor Center (S.Z.L.), University of Missouri, Columbia, Missouri.
authors.forename: Terry L
authors.initials: TL
authors.lastname: Carmack
authors.affiliation: Research Service, Harry S. Truman Memorial Veterans' Hospital, Columbia, Missouri (J.R.L., E.A.F.-C., L.D.W., T.L.C.); and Department of Radiology and Radiopharmaceutical Sciences Institute (J.R.L., E.A.F.-C., L.D.W., T.L.C.), Department of Medical Pharmacology and Physiology (J.R.L.), Department of Psychological Sciences (D.K.M., C.L.G.), Center for Translational Neuroscience (D.K.M.), Department of Chemistry (S.Z.L.), and MU Research Reactor Center (S.Z.L.), University of Missouri, Columbia, Missouri.
authors.forename: Susan Z
authors.initials: SZ
authors.lastname: Lever
mesh_terms: D000818:Animals; D001665:Binding Sites; D003042:Cocaine / Q000494:pharmacology*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism; D006168:Guinea Pigs; D006948:Hyperkinesis / Q000378:metabolism; D007555:Isoxazoles / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D008124:Locomotion / Q000187:drug effects; D008297:Male; D051379:Mice; D009044:Motor Cortex / Q000187:drug effects* / Q000378:metabolism; D009292:Narcotic Antagonists / Q000493:pharmacokinetics* / Q000494:pharmacology; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000378:metabolism; D011485:Protein Binding; D011725:Pyridines / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D017480:Receptors, sigma / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism; D000097605:Sigma-1 Receptor
chemical_list: D003042:Cocaine; D050483:Dopamine Plasma Membrane Transport Proteins; D007555:Isoxazoles; D009292:Narcotic Antagonists; D050484:Norepinephrine Plasma Membrane Transport Proteins; D011725:Pyridines; D017480:Receptors, sigma; D050486:Serotonin Plasma Membrane Transport Proteins; D000097605:Sigma-1 Receptor; C107238:1-propyl-5-(3-p-tolylisoxazol-5-yl)-1,2,3,6-tetrahydropyridine
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