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Euphorigenic doses of cocaine reduce [123I]β-CIT SPECT measures of dopamine transporter availability in human cocaine addicts

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Abstract

The in vivo potency of euphorigenic doses of intravenous cocaine for displacing [123I]β-CIT ([123I]2β-carbomethoxy-3β-(4-iodophenyl)tropane) binding to striatal dopamine transporters (DAT) was assessed in human cocaine addicts using single photon emission computed tomography (SPECT). Cocaine-dependent subjects (n=6) were injected with [123I]β-CIT and imaged 24 h later under equilibrium conditions. Sequential cocaine infusions (0.28±0.03 and 0.56±0.07 mg/kg) produced significant (P<0.0005) reductions in the specific to non-specific equilibrium partition coefficient, V3″ (6±6 and 17±3%), a measure proportional to DAT binding potential. Regression analysis of the logit transformed data enabled reliable determination of the Hill coefficient (0.51) and 50% displacement (ED50) dose of cocaine (2.8 mg/kg). These preliminary data suggest that cocaine produces behavioral effects in humans at measurable levels of DAT occupancy.

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References

  1. Baxter LR, Schwartz JM, Phelps ME, Mazziotta JC, Barrio J, Rawson RA, Engel J, Guze BH, Selin C, Sumida R (1988) Localization of neurochemical effects of cocaine and other stimulants in the human brain. J Clin Psychiatry 49 [Suppl]:23–6

  2. Boja JW, Patel A, Carroll FI, Rahman MA, Philip A, Lewin AH, Kopajtic TA, Kuhar MJ (1991) [125I] RTI-55: a potent ligand for dopamine transporters. Eur J Pharmacol 194:133–134

  3. Chow MJ, Ambre JJ, Ruo TI, Atkinson AJ, Bowsher DJ, Fischman MW (1985) Kinetics of cocaine distribution, elimination, and chronotropic effects. Clin Pharmacol Ther 38:318–324

  4. Edwards DJ, Bowles SK (1988) Protein binding of cocaine in human serum. Pharm Res 5:440–442

  5. Farde L, Halldin C, Muller L, Suhara T, Karlsson P, Hall H (1994) PET study of [11C]β-CIT binding to monoamine transporters in the monkey and human brain. Synapse 16:93–103

  6. Fowler JS, Volkow ND, Wolf AP, Dewey SL, Schlyer DJ, MacGregor RR, Hitzemann R, Logan J, Bendriem B, Gatley SJ, Christman D (1989) Mapping cocaine binding sites in human and baboon brain in vivo. Synapse 4:371–377

  7. Holman BL, Carvalho PA, Mendelson J, Teoh SK, Nardin R, Hallgring E, Hebben N, Johnson KA (1991) Brain perfusion is abnormal in cocaine-dependent polydrug users: a study using technetium-99m-HMPAO and ASPECT. J Nucl Med 32:1206–1210

  8. Koob GF, Bloom FE (1988) Cellular and molecular mechanisms of drug dependence. Science 242:715–723

  9. Kuhar M J, Ritz M C, Boja J W (1991) The dopamine hypothesis of the reinforcing properties of cocaine. Trends Neuroscie 14:299–302

  10. Laruelle M, Baldwin RM, Malison RT, Zea-Ponce Y, Zoghbi SS, Al-Tikriti MS, Sybirska EH, Zimmermann R, Wisniewski G, Neumeyer JL, Milius RA, Wang S, Smith EO, Roth RH, Charney DS, Hoffer PB, Innis RB (1993) SPECT imaging of dopamine and serotonin transporters with [123I]β-CIT: pharmacological characterization of brain uptake in nonhuman primates. Synapse 13:295–309

  11. Laruelle M, Giddings SS, Zea-Ponce Y, Charney DS, Neumeyer JL, Baldwin RM, Innis RB (1994a) Methyl 3β-(4-[125I]iodophenyl)tropane-2β-carboxylate in vitro binding to dopamine and serotonin transporters under “physiological” conditions. J Neurochem 62:978–986

  12. Laruelle M, Wallace E, Seibyl JP, Baldwin RM, Zea-Ponce Y, Zoghbi SS, Neumeyer JL, Charney DS, Hoffer PB, Innis RB (1994b) Graphical, kinetic, and equilibrium analyses of in vivo [123I]β-CIT binding to dopamine transporters in healthy human subjects. J Cereb Blood Flow Metab 14:982–994

  13. London ED, Cascella NG, Wong DF, Phillips RL, Dannals RF, Links JM, Herning R, Grayson R, Jaffe JH, Wagner HN (1990) Cocaine-induced reduction of glucose utilization in human brain: a study using positron emission tomography and [fluorine-18]-fluorodeoxyglucose. Arch Gen Psychiatry 47:567–574

  14. Madras BK, Fahey MA, Bergman J, Canfield DR, Spealman RD (1989) Effects of cocaine and related drugs in nonhuman primates. I. [3H]Cocaine binding sites in caudate-putamen. J Pharmacol Exp Ther 251:131–141

  15. Phelps ME, Huang SC, Hoffman EJ, Selin C, Sokoloff L, Kuhl DE (1979) Tomographic measurement of local cerebral glucose metabolic rate in humans with (F-18)2-fluoro-2-deoxy-D-glucose: validation of method. Ann Neurol 6:371–382

  16. Ritz MC, Lamb RJ, Goldberg SR, Kuhar MJ (1987) Cocaine receptors on dopamine transporters are related to self-administration of cocaine. Science 237:1219–1223

  17. Rothman RB (1990) High affinity dopamine reuptake inhibitors as potential cocaine antagonists: a strategy for drug development. Life Sci 46:L17–21

  18. van Dyck CH, Seibyl JP, Malison RT, Wallace E, Zoghbi SS, Zea-Ponce Y, Baldwin RM, Charney DS, Hoffer PB, Innis RB (1995) Age-related decline in dopamine transporter binding in human striatum with [123I]β-CIT SPECT. J Nucl Med 36:1175–1181

  19. Videbaek C, Friberg L, Holm S, Wammen S, Foged C, Andersen JV, Dalgaard L, Lassen NA (1993) Benzodiazepine receptor equilibrium constants for flumazenil and midazolam determined in humans with the single photon emission computer tomography tracer [123I]iomazenil. Eur J Pharmacol 249:43–51

  20. Volkow ND, Mullani N, Gould KL, Adler S, Krajewski K (1988) Cerebral blood flow in chronic cocaine users: a study with positron emission tomography. Br J Psychiatry 152:641–648

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Correspondence to Robert T. Malison.

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Malison, R.T., Best, S.E., McCance, E. et al. Euphorigenic doses of cocaine reduce [123I]β-CIT SPECT measures of dopamine transporter availability in human cocaine addicts. Psychopharmacology 122, 358–362 (1995). https://doi.org/10.1007/BF02246266

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Key words

  • [123I]β-CIT
  • Dopamine transporter
  • Cocaine
  • Medication development