Psychopharmacology

, Volume 119, Issue 4, pp 376–384

Rate of binding of various inhibitors at the dopamine transporter in vivo

  • M. Stathis
  • U. Scheffel
  • S. Z. Lever
  • J. W. Boja
  • M. J. Kuhar
  • F. I. Carroll
Original Investigation

DOI: 10.1007/BF02245852

Cite this article as:
Stathis, M., Scheffel, U., Lever, S.Z. et al. Psychopharmacology (1995) 119: 376. doi:10.1007/BF02245852

Abstract

The rate of entry of drugs into brain is thought to be a factor in their abuse liability. In this investigation, we have examined the rate of entry and binding at dopamine transporters in mouse striatum for a variety of dopamine transporter inhibitors. The method utilized was based on measuring the displacement of3H-WIN 35,428 from striatal dopamine transporter sites in vivo at different times. Eleven cocaine analogs (RTI-31, RTI-32, RTI-51, RTI-55, RTI-113, RTI-114, RTI-117, RTI-120, RTI-121, WIN 35,065-2, and WIN 35,428) as well as other dopamine uptake site blockers (bupropion, nomifensine, and methylphenidate) were compared with (−) cocaine for their rates of displacement of3H-WIN 35,428 binding in vivo. The drugs that displayed the fastest occupancy rates were bupropion, (−) cocaine, nomifensine, and methylphenidate. RTI-51, RTI-121, RTI-114, RTI-117, RTI-120, RTI-32, RTI-55, and RTI-113, showed intermediate rates, whereas RTI-31, WIN 35,065-2, and WIN 35,428 exhibited the slowest rates of displacement. While many of the cocaine analogs have proven to be behaviorally and pharmacologically more potent than (−) cocaine, their rates of entry and binding site occupancy were slower than that for (−) cocaine. Earliest times of transporter occupancy by the different drugs were correlated (although weakly) with their degree of lipophilicity (r=0.59;P<0.02). Kinetic effects and metabolism of the compounds could complicate the interpretations of these data. There was no obvious correlation between rate of occupancy in this animal model and abuse liability in humans, which is consistent with the notion that other factors are critical as well.

Key words

Dopamine transporter Cocaine analogs Mouse striatum 

Copyright information

© Springer-Verlag 1995

Authors and Affiliations

  • M. Stathis
    • 1
  • U. Scheffel
    • 1
  • S. Z. Lever
    • 2
  • J. W. Boja
    • 3
  • M. J. Kuhar
    • 3
  • F. I. Carroll
    • 4
  1. 1.Department of Radiology, Division of Nuclear MedicineJohns Hopkins University School of MedicineBaltimoreUSA
  2. 2.Department of Environmental Health Services, Division of Radiation HealthJohns Hopkins University School of Hygiene and Public HealthBaltimoreUSA
  3. 3.Addiction Research Center, Neuroscience BranchNational Institute on Drug AbuseBaltimoreUSA
  4. 4.Research Triangle InstituteChemistry and Life SciencesResearch Triangle ParkUSA

Personalised recommendations