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Research ArticleBehavioral Pharmacology

Relationship between Cerebral Sigma-1 Receptor Occupancy and Attenuation of Cocaine’s Motor Stimulatory Effects in Mice by PD144418

John R. Lever, Dennis K. Miller, Emily A. Fergason-Cantrell, Caroline L. Green, Lisa D. Watkinson, Terry L. Carmack and Susan Z. Lever
Journal of Pharmacology and Experimental Therapeutics October 2014, 351 (1) 153-163; DOI: https://doi.org/10.1124/jpet.114.216671
John R. Lever
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
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Dennis K. Miller
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
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Emily A. Fergason-Cantrell
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
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Caroline L. Green
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
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Lisa D. Watkinson
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
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Terry L. Carmack
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
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Susan Z. Lever
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
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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 (r2 = 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.

Footnotes

    • Received May 15, 2014.
    • Accepted August 5, 2014.
  • This work was supported by the National Institutes of Health National Institute on Drug Abuse [Grant 1RC1-DA028477 to J.R.L.]; by facilities and resources provided by the Harry S. Truman Memorial Veterans’ Hospital; and by the University of Missouri Life Sciences Mission Enhancement Program. J.R.L. is the guarantor of the work, had access to all data, and takes responsibility for data integrity and analysis.

  • Primary laboratory of origin: Research Service, Harry S. Truman Memorial Veterans’ Hospital, Columbia, Missouri (J.R.L.).

  • dx.doi.org/10.1124/jpet.114.216671.

  • U.S. Government work not protected by U.S. copyright
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Journal of Pharmacology and Experimental Therapeutics: 351 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 351, Issue 1
1 Oct 2014
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Research ArticleBehavioral Pharmacology

PD144418 Blocks Cocaine-Induced Locomotor Hyperactivity

John R. Lever, Dennis K. Miller, Emily A. Fergason-Cantrell, Caroline L. Green, Lisa D. Watkinson, Terry L. Carmack and Susan Z. Lever
Journal of Pharmacology and Experimental Therapeutics October 1, 2014, 351 (1) 153-163; DOI: https://doi.org/10.1124/jpet.114.216671

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Research ArticleBehavioral Pharmacology

PD144418 Blocks Cocaine-Induced Locomotor Hyperactivity

John R. Lever, Dennis K. Miller, Emily A. Fergason-Cantrell, Caroline L. Green, Lisa D. Watkinson, Terry L. Carmack and Susan Z. Lever
Journal of Pharmacology and Experimental Therapeutics October 1, 2014, 351 (1) 153-163; DOI: https://doi.org/10.1124/jpet.114.216671
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