, Volume 180, Issue 3, pp 408–413

Characterization of conditioned place preference to cocaine in congenic dopamine transporter knockout female mice

  • Ivan O. Medvedev
  • Raul R. Gainetdinov
  • Tatyana D. Sotnikova
  • Laura M. Bohn
  • Marc G. Caron
  • Linda A. Dykstra
Original Investigation



The dopamine transporter (DAT) is thought to play a major role in the rewarding effects of cocaine. Therefore, it is surprising that cocaine reveals conditioned effects in DAT knockout (DAT-KO) mice.


To examine these findings further, we obtained complete dose–effect curves for DAT-KO and DAT wild-type (DAT-WT) mice in a cocaine conditioned place preference (CPP) procedure.


Congenic C57BL6 background female DAT-KO and DAT-WT mice were conditioned in a three-compartment place preference apparatus. Conditioning consisted of three 30-min sessions with cocaine (2.5, 5.0, 10.0, 20.0, or 40.0 mg/kg) and three 30-min sessions with saline. The distribution of time in each choice compartment was determined after each pair of conditioning sessions (one cocaine and one saline session).


DAT-WT mice revealed CPP over a wide range of cocaine doses (5.0–40 mg/kg), whereas DAT-KO mice revealed CPP over a more restricted range of doses, with consistent CPP only occurring with 10 mg/kg of cocaine.


CPP for cocaine develops in both DAT-KO and DAT-WT mice; however, the dose range at which CPP develops is much more restricted in DAT-KO mice than in DAT-WT mice. These observations corroborate the significant role of DAT inhibition in cocaine’s conditioned effects.


Cocaine Dopamine Knockout mice Dopamine transporter Conditioned place preference Reward 


  1. Bardo MT, Rowlett JK, Harris MJ (1995) Conditioned place preference using opiate and stimulant drugs: a meta-analysis. Neurosci Biobehav Rev 19:39–51CrossRefPubMedGoogle Scholar
  2. Bespalov AY, Tokarz ME, Bowen SE, Balster RL, Beardsley PM (1999) Effects of test conditions on the outcome of place conditioning with morphine and naltrexone in mice. Psychopharmacology 141:118–122Google Scholar
  3. Bohn LM, Gainetdinov RR, Sotnikova TD, Medvedev IO, Lefkowitz RJ, Dykstra LA, Caron MG (2003) Enhanced rewarding properties of morphine, but not cocaine, in barrestin-2 knockout mice. J Neurosci 23:10265–10273Google Scholar
  4. Budygin EA, John CE, Mateo Y, Jones SR (2002) Lack of cocaine effect on dopamine clearance in the core and shell of the nucleus accumbens of dopamine transporter knock-out mice. J Neurosci 22(RC222):1–4PubMedGoogle Scholar
  5. Carboni E, Spielewoy C, Vacca C, Nosten-Bertrand M, Giros B, Di Chiara G (2001) Cocaine and amphetamine increase extracellular dopamine in the nucleus accumbens of mice lacking the dopamine transporter gene. J Neurosci 21(RC141):1–4Google Scholar
  6. Cunningham CL, Dickinson SD, Grahame NJ, Okorn DM, McMullin CS (1999) Genetic differences in cocaine-induced conditioned place preference in mice depend on conditioning trail duration. Psychopharmacology 146:73–80Google Scholar
  7. Di Chiara G, Imperato A (1988) Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats. Proc Natl Acad Sci 85:5274–5278Google Scholar
  8. Gainetdinov RR, Caron MG (2003) Monoamine transporters: from genes to behavior. Annu Rev Pharmacol Toxicol 43:261–284Google Scholar
  9. Gainetdinov RR, Wetsel WC, Jones SR, Levin ED, Jaber M, Caron MG (1999) Role of serotonin in the paradoxical calming effect of psychostimulants on hyperactivity. Science 283:397–401CrossRefPubMedGoogle Scholar
  10. Gainetdinov RR, Sotnikova TD, Caron MG (2002) Monoamine transporter pharmacology and mutant mice. Trends Pharmacol Sci 23(8):367–373Google Scholar
  11. Giros B, Jaber M, Jones SR, Wightman RM, Caron MG (1996) Hyperlocomotion and indifference to cocaine and amphetamine in mice lacking the dopamine transporter. Nature 379:606–612CrossRefPubMedGoogle Scholar
  12. He M, Shippenberg TS (2000) Strain differences in basal and cocaine-evoked dopamine dynamics in mouse striatum. J Pharmacol Exp Ther 293:121–127Google Scholar
  13. Hollerman JR, Schultz W (1998) Dopamine neurons report an error in the temporal prediction of reward during learning. Nat Neurosci 1:304–309Google Scholar
  14. Jones SR, Gainetdinov RR, Jaber M, Giros B, Wightman RM, Caron MG (1998) Profound neuronal plasticity in response to inactivation of the dopamine transporter. Proc Natl Acad Sci 95:4019–4034Google Scholar
  15. Kuhar MJ (1998) Recent biochemical studies of the dopamine transporter—a CNS drug target. Life Sci 62:1573–1575Google Scholar
  16. Laakso A, Mohn AR, Gainetdinov RR, Caron MG (2002) Experimental genetic approaches to addiction. Neuron 36:213–228Google Scholar
  17. Lynch WJ, Carrol ME (1999) Sex differences in the acquisition of intravenously self-administered cocaine and heroine in rats. Psychopharmacology 144:77–82CrossRefPubMedGoogle Scholar
  18. Mateo Y, Budygin EA, John CE, Jones SR (2003) Role of serotonin in cocaine effects in mice with reduced dopamine transporter function. Proc Natl Acad Sci 101:372–377Google Scholar
  19. Mead AN, Rocha BA, Donovan DM, Katz JL (2002) Intravenous cocaine induced-activity and behavioural sensitization in norepinephrine-, but not dopamine-transporter knockout mice. Eur J Neurosci 16:514–520Google Scholar
  20. Phillips PE, Stuber GD, Heien ML, Wightman RM, Carelli RM (2003) Subsecond dopamine release promotes cocaine seeking. Nature 422:614–618Google Scholar
  21. Ralph RJ, Paulus MP, Fumagalli F, Caron MG, Geyer MA (2001) Prepulse inhibition deficits and perseverative motor patterns in dopamine transporter knock-out mice: differential effects of D1 and D2 receptor antagonists. J Neurosci 21:305–313Google Scholar
  22. Ritz MC, Lamb RJ, Goldberg SR, Kuhar MJ (1987) Cocaine receptors on dopamine transporters are related to self-administration of cocaine. Science 237:1219–1223PubMedGoogle Scholar
  23. Robinson DL, Phillips PE, Budygin EA, Trafton BJ, Garris PA, Wightman RM (2001) Sub-second changes in accumbal dopamine during sexual behavior in male rats. NeuroReport 12:2549–2552CrossRefPubMedGoogle Scholar
  24. Rocha BA, Fumagalli F, Gainetdinov RR, Jones SR, Ator R, Giros B, Miller GW, Caron MG (1998) Cocaine self-administration in dopamine-transporter knockout mice. Nat Neurosci 1:132–137Google Scholar
  25. Roitman MF, Stuber GD, Phillips PE, Wightman RM, Carelli RM (2004) Dopamine operates as a subsecond modulator of food seeking. J Neurosci 24:1265–1271CrossRefPubMedGoogle Scholar
  26. Russo SJ, Jenab S, Fabian SJ, Festa ED, Kemen LM, Quinones-Jenab V (2003) Sex differences in the conditioned rewarding effects of cocaine. Brain Res 970:214–220CrossRefPubMedGoogle Scholar
  27. Sershen H, Hashim A, Lajtha A (1998) Gender differences in kappa-opioid modulation of cocaine-induced behavior and NMDA-evoked dopamine release. Behav Res 801:67–71Google Scholar
  28. Sora I, Wichems C, Takahashi N, Li XF, Zeng A, Revay R, Lesch KP, Murphy D, Uhl GR (1998) Cocaine reward models: conditioned place preference can be established in dopamine- and in serotonin-transporter knockout mice. Proc Natl Acad Sci 95:7699–7704Google Scholar
  29. Sora I, Hall FS, Andrews AM, Itokawa M, Li XF, Wei HB, Wichems C, Lesch KP, Murphy DL, Uhl GR (2001) Molecular mechanisms of cocaine reward: combined dopamine and serotonin transporter knockouts eliminate cocaine place preference. Proc Natl Acad Sci 98:5300–5305Google Scholar
  30. Spielewoy C, Roubert C, Hamon M, Nosten-Bertrand M, Betancur C, Giros B (2000) Behavioural disturbances associated with hyperdopaminergia in dopamine-transporter knockout mice. Behav Pharmacol 11:279–290Google Scholar
  31. Tzschentke RM (1998) Measuring reward with the conditioned place preference paradigm: a comprehensive review of drug effects, recent progress and new issues. Prog Neurobiol 56:613–672CrossRefPubMedGoogle Scholar
  32. Volkow ND, Wang GJ, Fischman MW, Foltin RW, Fowler JS, Abumrad NN, Vitkun S, Logan J, Gatley SJ, Pappas N, Hitzemann R, Shea CE (1997) Relationship between subjective effects of cocaine and dopamine transporter occupancy. Nature 386:827–830Google Scholar
  33. Waelti P, Dickinson A, Schultz W (2001) Dopamine responses comply with basic assumptions of formal learning theory. Nature 412:43–48CrossRefPubMedGoogle Scholar
  34. Wise RA (1998) Drug-activation of brain reward pathways. Drug Alcohol Depend 51:13–22CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2005

Authors and Affiliations

  • Ivan O. Medvedev
    • 1
  • Raul R. Gainetdinov
    • 1
  • Tatyana D. Sotnikova
    • 1
  • Laura M. Bohn
    • 2
  • Marc G. Caron
    • 1
  • Linda A. Dykstra
    • 3
  1. 1.Department of Cell BiologyDuke University Medical CenterDurhamUSA
  2. 2.Department of PharmacologyThe Ohio State University College of Medicine and Public HealthColumbusUSA
  3. 3.Department of PsychologyUniversity of North Carolina at Chapel HillChapel HillUSA

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