Cocaine is believed to work by blocking the dopamine transporter (DAT) and thereby increasing the availability of free dopamine within the brain1–4. Although this concept is central to current cocaine research and to treatment development, a direct relationship between DAT blockade and the subjective effects of cocaine has not been demonstrated in humans. We have used positron emission tomography to determine what level of DAT occupancy is required to produce a subjective 'high' in human volunteers who regularly abuse cocaine. We report here that intravenous cocaine at doses commonly abused by humans (0.3–0.6 mg kg−1) blocked between 60 and 77% of DAT sites in these subjects. The magnitude of the self-reported high was correlated with the degree of DAT occupancy, and at least 47% of the transporters had to be blocked for subjects to perceive cocaine's effects. Furthermore, the time course for the high paralleled that of cocaine concentration within the striatum, a brain region implicated in the control of motivation and reward. This is the first demonstration in humans that the doses used by cocaine abusers lead to significant blockade of DAT, and that this blockade is associated with the subjective effects of cocaine. Although these findings provide justification to target the DAT for medication development they suggest that for drugs to be effective in blocking cocaine's effects they would have to be given at doses that achieve almost complete DAT occupancy.
Access optionsAccess options
Subscribe to Journal
Get full journal access for 1 year
only $3.90 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Ritz, M. C., Lamb, R. J., Goldberg, S. R. & Kuhar, M. J. Cocaine receptors on dopamine transporters are related to self-administration of cocaine. Science 237, 1219–1223 (1987).
Koob, G. F. & Bloom, F. E. Cellular and molecular mechanism of drug dependence. Science 242, 715–723 (1988).
Madras, B. K., Fahey, M. A., Bergman, J., Canfield, D. R. & Spealman, R. D. Effects of cocaine and related drugs in non-human primates. I: [3H]cocaine binding sites in caudate-putamen. J. Pharmacol. Exp. Ther. 251, 131–141 (1989).
Giros, B., Jaber, M., Jones, S. R., Wightman, R. M. & Caron, M. G. Hyperlocomotion and indifference to cocaine and amphetamine in mice lacking the dopamine transporter. Nature 379, 606–612 (1996).
Fowler, J. et al. Mapping cocaine-binding sites in human and baboon brain in vivo. Synapse 4, 371–377 (1989).
Pogun, S., Scheffel, U. & Kuhar, M. J. Cocaine displaces 3H-WIN 35,248 binding to dopamine uptake sites in vivo more rapidly than mazindol or GBR 12,909. Eur. J. Pharmacol. 198, 203–205 (1991).
Gatley, S. J. et al. Displacement of RTI-55 from the dopamine transporter by cocaine. Eur. J. Pharmacol. 296, 145–151 (1996).
Logan, J. et al. Effects of blood flow on [11C] raclopride binding in the brain: model simulations and kinetic analysis of PET data. J. Cereb. Blood Flow Metab. 14, 995–1010 (1994).
Nestler, E. J. Molecular mechanisms of drug addiction. J. Neurosci. 12, 2439–2450 (1992).
Volkow, N. D. et al. Temporal relationships between the pharmacokinetics of methylphenidate in the human brain and its behavioral and cardiovascular effects. Psychopharmacology 123, 26–33 (1996).
Fischman, M. W. & Foltin, R. W. Utility of subjective-effects measurements in assessing abuse liability of drugs in humans. Br. J. Addiction 86, 1563–1570 (1991).
Fischman, M. W. in Testing for Abuse Liability of Drugs in Humans, NIDA Research Monographs Vol. 92 (eds Fischman, M. W. & Mello, N. H.) 211–230 (Government Printing Office, Washington DC, 1989).
Pettit, H. O. & Justice, J. B. Effect of dose in cocaine self-administration behavior and dopamine levels in the nucleus accumbens. Brain Res. 539, 94–102 (1991).
Balster, R. L. & Schuster, C. R. Fixed interval schedule of cocaine reinforcement: effect of dose and infusion duration. J. Exp. Anal. Behav. 20, 119–129 (1973).
Stathis, M. et al. Rate of binding of various inhibitors at the dopamine transporter in vivo. Psychopharmacology 119, 376–384 (1995).
Verbey, K. & Gold, M. S. From coca leaves to crack: the effects of dose and routes of administration in abuse liability. Psychiatr. Ann. 18, 513–520 (1988).
Rothman, R. B. High affinity dopamine reuptake inhibitors as potential cocaine antagonists: a strategy for drug development. Life Sci. 46, 17–21 (1990).
Pettit, H. O., Ettenberg, A., Bloom, F. E. & Koob, G. F. Destruction of dopamine in the nucleus accumbens selectively attentuates cocaine but not heroin self-administration in rats. Psychopharmacology 84, 167–173 (1984).
Pontieri, F. E., Tanda, G., Orzi, F. & Di Chiara, G. Effects of nicotine on the nucleus accumbens and similarity to those of addictive drugs. Nature 382, 255–257 (1996).
Izenwasser, S., Werling, L. L. & Cox, B. M. Comparison of the effects of cocaine and other inhibitors of dopamine uptake in rat striatum, nucleus accumbens, olfactory tubercle, and medial prefrontal cortex. Brain Res. 520, 303–309 (1990).
Javaid, J. L., Fischman, M. W., Schuster, C. R., Dekirmenjiian, H. & Davis, J. M. Cocaine plasma concentration: relation to physiological and subjective effects in human. Science 202, 227–228 (1978).
Gatley, S. J. et al. A model for estimating dopamine transporter occupancy and subsequent increases in synaptic dopamine using positron emission tomography and carbon-11 labeled cocaine. Biochem. Pharmacol. 51, 43–52 (1997).
Volkow, N. D. et al. Carbon-11-cocaine binding compared at sub-pharmacological and pharmacological doses: a PET study. J. Nucl. Med. 36, 1289–1297 (1995).
Logan, J. et al. Graphical analysis of reversible radioligand binding from time-activity measurements applied to [N-11C-methyl]-(l)-cocainePETstudies in human subjects. J. Cereb. Blood Flow Metab. 10, 740–747 (1990).
About this article
PLOS ONE (2019)
A Novel Neurobehavioral Framework of the Effects of Positive Early Postnatal Experience on Incentive and Consummatory Reward Sensitivity
Neuroscience & Biobehavioral Reviews (2019)
Frontiers in Psychiatry (2019)
Quantitative Systems Pharmacological Analysis of Drugs of Abuse Reveals the Pleiotropy of Their Targets and the Effector Role of mTORC1
Frontiers in Pharmacology (2019)
Where Is Dopamine and how do Immune Cells See it?: Dopamine-Mediated Immune Cell Function in Health and Disease
Journal of Neuroimmune Pharmacology (2019)