Skip to main content
SpringerLink
Log in

The dopamine D3 receptor and drug addiction

  • Published:
Neurotoxicity Research Aims and scope Submit manuscript

Abstract

Hedonic and reinforcing properties of drugs of abuse are closely related to brain dopamine neuron activity. All these drugs increase dopamine release in the shell of nucleus accumbens, a brain region in which neurons co-express the D1 (D1R) and D3 (D3R) dopamine receptor subtypes, that converging pharmacological, human post-mortem and genetic studies suggest to be implicated in drug addiction. The D3R, through a cross-talk with the D1R, is involved in induction and expression of behavioral sensitization to levodopa in rats bearing unilateral lesions of dopamine neurons. Behavioral sensitization, a cardinal feature of addiction arises from repeated administration of drugs of abuse is thought to play a role in intensification of reinforcing efficacy of these drugs observed under certain conditions. Stimulation of the D3R also appears to enhance the reinforcing effect of cocaine in rats. By interacting with these processes, D3R agents have potential therapeutic applications for treating drug addiction. BP 897 (N-[4-(4-(2-methoxyphenyl) piperazin-1-yl) butyl] naphtalen 2-carboxamide dichlorhydrate), a partial and highly selective D3R agonistin vitro, behaves as an agonist or an antagonistin vivo depending on the response considered. BP 897 has the unprecedented property to reduce cocaine-seeking behavior induced by presentation of a cocaine-associated cue, without having any intrinsic reinforcing effect. As drug-associated cues maintain drug-seeking in animals and elicit craving and relapse in humans, D3R agents like BP 897 may represent new medications for drug addiction, with minimal liability to maintaining dependence.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Altaian, J., Everitt, B.J., Glautier, S., Markou, A., Nutt, D., Oretti, R., Phillips, G.D. and Robbins, T.W. (1996) The biological, social and clinical bases of drug addiction: commentary and debate. Psychopharmacology (Berl). 125, 285–345.

    Article  Google Scholar 

  • Arroyo, M., Markou, A., Robbins, T.W. and Everitt, BJ. (1999) Acquisition, maintenance and reinstatement of intravenous cocaine self-administration under a second-order schedule of reinforcement in rats: effects of conditioned cues and continuous access to cocaine. Psychopharmacology. 140, 331–344.

    Article  Google Scholar 

  • Bordet, R., Ridray, S., Carboni, S., Diaz, J., Sokoloff, P. and Schwartz, J.-C. (1997) Induction of dopamine D3 receptor expression as a mechanism of behavioral sensitization to levodopa. Proc Natl Acad Sci USA. 94, 3363–3367.

    Article  PubMed  CAS  Google Scholar 

  • Bordet, R., Ridray, S., Schwartz, J.-C. and Sokoloff, P. (2000) Involvement of the direct striatonigral pathway in levo-dopa-induced sensitization in 6-hydroxy-dopamine-lesioned rats.Involvement of the direct striatonigral pathway in levo-dopa-induced sensitization in 6-hydroxy-dopamine-lesioned rats 12, 2117–2123.

    CAS  Google Scholar 

  • Bouthenet, M.-L., Souil, E., Martres, M.-P., Sokoloff, P., Giros, B. and Schwartz, J.-C. (1991) Localization of dopamine D3 receptor mRN A in the rat brain using in situ hybridization histochemistry: comparison withGJ receptor mRNA. Brain Res. 564, 203–219.

    Article  PubMed  CAS  Google Scholar 

  • Cabib, S., Castellano, C, Cestari, V., Filibeck, U. and Puglisi-Allegra, S. (1991) Dl and D2 receptor antagonists differently affect cocaine-induced locomotor hyperactivity in the mouse. Psychopharmacology (Berl). 105, 335–339.

    Article  CAS  Google Scholar 

  • Caine, S.B. and Koob, G.F. (1993) Modulation of cocaine self-administration in the rat through D3dopamine receptors. Science. 260, 1814–1816.

    Article  PubMed  CAS  Google Scholar 

  • Caine, S.B. and Koob, G.F. (1994) Effects of dopamine D-l and D-2 antagonists on cocaine self-administration under different schedules of reinforcement in the rat. J Pharmacol Exp Ther. 270, 209–218.

    PubMed  CAS  Google Scholar 

  • Caine, S.B. and Koob, G.F. (1995) Pretreatment with the dopamine agonist 7-OH-DPAT shifts the cocaine self-administration dose-effect function to the left under different schedules in the rat. Behavioural Pharmacology. 6, 333–347.

    Article  PubMed  CAS  Google Scholar 

  • Caine, S.B., Koob, G.F., Parsons, L.H., Everitt, B.J., Schwartz, J.-C. and Sokoloff, P. (1997) D3receptor testin vitro predicts decreased cocaine self-administration in rats. Neu-roreport. 8, 2373–2377.

    CAS  Google Scholar 

  • Carey, R.J. Chronic L-DOPA treatment in the unilateral 6-OHDA rat: evidence for behavioral sensitization and biochemical tolerance. Brain Res. 568, 205–214.

  • Childress, E. R., Roohsenow, D.J., Robbins, S.H. and O’Brien, C.P. (1992). Classically conditioned factors in drug dependence. (Ed) Substance abuse: a comprehensive text book (Baltimore: Williams and Wilkins), pp 56–69.

    Google Scholar 

  • Cole, R.L., Konradi, C, Douglass, J. and Hyman, S.E. (1995) Neuronal adaptation to amphetamine and dopamine: molecular mechanisms of prodynorphin gene regulation in rat striatum. Neuron. 14, 813–823.

    Article  PubMed  CAS  Google Scholar 

  • de Wit, H. and Stewart, J. (1981) Reinstatement of cocaine-reinforced responding in the rat. Psychophar-macol. 75, 134–143.

    Article  Google Scholar 

  • Di Chiara, G. and Imperato, A. (1988) Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats. Proc Natl Acad Sci USA. 85, 5274–5278.

    Article  PubMed  Google Scholar 

  • Diaz, J., Levesque, D., Lammers, C.H., Griffon, N., Martres, M.-P., Schwartz, J.-C. and Sokoloff, P. (1995) Phenotypi-cal characterization of neurons expressing the dopamine D3 receptor. Neuroscience. 65, 731–745.

    Article  PubMed  CAS  Google Scholar 

  • Drago, J., Gerfen, C.R., Westphal, H. and Steiner, H. (1996) Dj dopamine receptor-deficient mouse: cocaine-induced regulation of immediate-early gene and substance P expression in the striatum. Neuroscience. 74, 813–823.

    Article  PubMed  CAS  Google Scholar 

  • Duaux, E., Gorwood, P., Sautel, F., Griffon, N., Sokoloff, P., Schwartz, J.-C, Olie, J.-P., Lo, H. and Poirier, M.-F. (1998) Homozygosity at the dopamine D3receptor gene is associated with opioid dependence. Mol Psychiatry. 3, 333–336.

    Article  PubMed  CAS  Google Scholar 

  • Engber, T.M., Suzel, Z., Juncos, J.L. and Chase, T.N. (1989) Continuous and intermittent levodopa differentially affect rotation induced by Dj and D2 dopamine agonists. Brain Res. 552, 113–118.

    Article  Google Scholar 

  • Fontana, D.J., Post, R.M. and Pert, A. (1993) Conditioned increases in mesolimbic dopamine overflow by stimuli associated with cocaine. Brain Res. 629, 31–39.

    Article  PubMed  CAS  Google Scholar 

  • Grech, D.M., Spealman, R.D. and Bergman, J. (1996) Self-administration of Dj receptor agonists by squirrel monkeys. Psychopharmacology. 125, 97–104.

    Article  PubMed  CAS  Google Scholar 

  • Griffon, N., Pilon, C, Sautel, F., Schwartz, J.-C. and Sokoloff, P. (1997) Two intracellular pathways for the dopamine D3 receptor: opposite and synergistic interactions with cyclic AMP. J Neurochem. 67, 1–9.

    Google Scholar 

  • Heimer, L., Zham, D.S. and Alheid, G.F. (1995). Basal ganglia. (Ed) The Rat Nervous System (New York: Academic Press), pp 579–628.

    Google Scholar 

  • Horger, B.A., Shelton, K. and Schenk, S. (1990) Preexposure sensitizes rats to the rewarding effects of cocaine. Pharmacol Biochem Behav. 37, 707–711.

    Article  PubMed  CAS  Google Scholar 

  • Kalivas, P.W. and Stewart, J. (1991) Dopamine transmission in the initition and expression of drug- and stress-induced sensitization of motor activity. Brain Res Rev;. 16, 223–244.

    Article  PubMed  CAS  Google Scholar 

  • Koob, G.F. (1992) Dopamine, addiction and reward. Sem Neurosci. 4, 139–148.

    Article  Google Scholar 

  • Krebs, M.-O., Sautel, F., Bourdel, M.-C, Sokoloff, P., Schwartz, J.-C, Olie, J.-P., Loo, H. and Poirier, M.-F. (1998) Dopamine D3 receptor gene variants and substance abuse in schizophrenia. Mol Psychiatry. 3, 337–341.

    Article  PubMed  CAS  Google Scholar 

  • Lamas, X., Negus, S.S., Nader, M.A. and Mello, N.K. (1996) Effects of putative dopamine D3 receptor agonist 7-OH-DPAT in rhesus monkeys trained to discriminate cocaine from saline. Psychopharmacology (Berl). 124, 306–314.

    Article  CAS  Google Scholar 

  • Le Foil, B., Schwartz J.C. and Sokoloff P. (2000) Dopamine D3 receptor agents as potential new medications for drug addiction. Eur Psychiatry. 15, 140–6.

    Article  Google Scholar 

  • Lett, B.T. (1989) Repeated exposures intensify rather than diminish the rewarding effects of amphetamine, morphine and cocaine. Psychopharmacology. 98, 357–362.

    Article  PubMed  CAS  Google Scholar 

  • Levesque, D., Diaz, J., Pilon, C, Martres, M.-P., Giros, B., Souil, E., Schott, D., Morgat, J.-L., Schwartz, J.-C. and Sokoloff, P. (1992) Identification, characterization and localization of the dopamine D3 receptor in rat brain using 7-[3H]-hydroxy-N,N di-n-propyl-2-aminotetralin. Proc Natl Acad Sci USA. 89, 8155–8159.

    Article  PubMed  CAS  Google Scholar 

  • Levesque, D., Martres, M.-P., Diaz, J., Griffon, N., Lammers, C.H., Sokoloff, P. and Schwartz, J.-C. (1995) A paradoxical regulation of the dopamine D3 receptor expression suggests the involvement of an anterograde factor from dopamine neurons. Proc Natl Acad; Sci USA. 92, 1719–1723.

    Article  PubMed  CAS  Google Scholar 

  • Maldonado, R., Robledo, P., Chover, A.J., Caine, S.B. and Koob, G.F. (1993) Dl dopamine receptors in the nucleus accumbens modulate cocaine self-administration in the rat. Pharmacol Biochem Behav. 45, 239–242.

    Article  PubMed  CAS  Google Scholar 

  • Meil, W.M. and See, R.E. (1996) Conditioned cue recovery of responding following prolonged withdrawal from self-administered cocaine in rats: an animal model of relapse. Behav Pharmacol. 7, 754–763.

    PubMed  CAS  Google Scholar 

  • Meil, W.M. and See, R.E. (1997) Lesions of the basolateral amygdala abolish the ability of drug associated cues to reinstate responding during withdrawal from self-administered cocaine. Behav Brain Res. 87, 139–148.

    Article  PubMed  CAS  Google Scholar 

  • Milner, P.M. (1991) Brain-stimulation reward: a review. Can J Psychol. 45, 1–36.

    PubMed  CAS  Google Scholar 

  • Morelli, M., Cozzolino, A., Pinna A., Fenu, S., Carta, A. and Di Chiara, G. (1993) L-dopa stimulates c-fos expression in dopamine denervated striatum by combined activation of Dl and D2 receptors. Brain Res. 623, 334–6.

    Article  PubMed  CAS  Google Scholar 

  • Moratalla, R., Xu, M., Tonegawa, S. and Graybiel, A.M. (1996) Cellular responses to psychomotor stimulant and neuroleptic drugs are abnormal in mice lacking the Dl dopamine receptor. Proc Natl Acad Sci USA. 93, 14928–14933.

    Article  PubMed  CAS  Google Scholar 

  • Nestler, E.J. (1992) Molecular mechanisms of drug addiction. J Neuroscience. 12, 2439–2450.

    CAS  Google Scholar 

  • O’Brien, C.P., Childress, A.R., McMellan, A.T. and Ehrman, R.A. (1992) A learning model of addiction. Res Publ Assoc Res Nerv Ment Dis. 70, 157–177.

    PubMed  CAS  Google Scholar 

  • O’Brien, C.P. and McMellan, A.T. (1996) Myths about the treatment of addiction. Lancet. 347, 237–240.

    Article  PubMed  CAS  Google Scholar 

  • Pennartz, CM., Groenewegen, H.J. and Lopes da Silva, F.H. (1994) The nucleus accumbens as a complex of functionally distinct neuronal ensembles: an integration of behavioural, electrophysiological and anatomical data. Prog Neurobiol. 42, 719–761.

    Article  PubMed  CAS  Google Scholar 

  • Pilla, M., Perachon, S., Sautel, F., Garrido, F., Mann, A., Wer-muth, C.G., Schwartz, J.-C., Everitt, B.J. and Sokoloff, P. (1999) Selective inhibition of cocaine-seeking behaviour by a partial dopamine D3 receptor agonist. Nature. 400, 371–375.

    Article  PubMed  CAS  Google Scholar 

  • Pilon, C., Levesque, D., Dimitriadou, V., Griffon, N., Martres, M.P., Schwartz, J.-C. and Sokoloff, P. (1994) Functional coupling of the human dopamine D3 receptor in a trans-fected NG 108-15 neuroblastoma-glioma hybrid cell line. Eur J Pharmacol [Mol Pharmacol Sect]. 268, 129–139.

    PubMed  CAS  Google Scholar 

  • Pulverenti, L. and Koob, G.F. (1994) Dopamine agonists, partial agonists and psychostimulant addiction. Trends Pharmacol Sci. 15, 374–379.

    Article  Google Scholar 

  • Ridray, S., Griffon, N., Souil, E., Mignon, V., Carboni, S., Diaz, J., Schwartz, J.-C. and Sokoloff, P. (1998) Coexpres-sion of dopamine Dj and D3 receptors in rat ventral striatum: opposite and synergistic functional interactions. Eur J Neurosci. 10, 1676–1686.

    Article  PubMed  CAS  Google Scholar 

  • Sautel, F., Griffon, N., Sokoloff, P., Schwartz, J.-C, Launay, C, Simon, P., Costentin, J., Schoenfelder, A., Garrido, F., Mann, A. and Wermuth, C.G. (1995) Nafadotride, a potent preferential dopamine D3 receptor antagonist, activates locomotion in rodents. J Pharmacol Exp Ther. 275, 1239–1246.

    PubMed  CAS  Google Scholar 

  • Segal, D.M., Moraes, C.T. and Mash, D.C. (1997) Up-regula-tion of D3 dopamine receptor mRNA in the nucleus accumbens of human cocaine fatalities. Mol Brain Res. 45, 335–339.

    Article  PubMed  CAS  Google Scholar 

  • Self, D.W. and Nestler, E.J. (1988) Relapse to drug-seeking: neural and molecular mechanisms. Drug Alcohol Dep. 51, 49–60.

    Article  Google Scholar 

  • Sokoloff, P., Giros, B., Martres, M.-P., Bouthenet, M.-L. and Schwartz, J.-C. (1990) Molecular cloning and characterization of a novel dopamine receptor (D3) as a target for neuroleptics. Nature. 347, 146–151.

    Article  PubMed  CAS  Google Scholar 

  • Spealman, R.D. (1996) Dopamine D3 receptor agonists partially reproduce the discriminative stimulus effects of cocaine in squirrel monkeys. J Pharmacol Exp Ther. 278, 1128–1137.

    PubMed  CAS  Google Scholar 

  • Spealman, R.D., Bergman, J., Madras, B.K. and Melia, K.F. (1991) Discriminative stimulus effects of cocaine in squirrel monkeys: involvement of dopamine receptor subtypes. J Pharmacol Exp Ther. 258, 945–953.

    PubMed  CAS  Google Scholar 

  • Staley, J.K. and Mash, D.C. (1996) Adaptive increase in D3 dopamine receptors in the brain reward circuits of human cocaine fatalities. J Neuroscience. 16, 6100–6106.

    CAS  Google Scholar 

  • Stewart, J. (1983) Conditioned and unconditioned drug effects in relapse to opiate and stimulant drug-administration. Prog Neuropsychopharmacol Biol Psychiatry. 7, 591–597.

    Article  PubMed  CAS  Google Scholar 

  • Telia, S.R. (1994) Differential blockade of chronic versus acute effects of intravenous cocaine by dopamine receptor antagonists. Pharmacol Biochem Behav. 48, 151–159.

    Article  Google Scholar 

  • Whitelaw, R.B., Markou, A., Robbins, T.W. and Everitt, B.J. (1996) Excitotoxic lesions of the basolateral amygdala impair the acquisition of cocaine-seeking behaviour under a second-order schedule of reinforcement. Psy-chopharmacology. 127, 213–224.

    CAS  Google Scholar 

  • Wikler, A. (1973) Dynamics of drug dependence. Arch Gen Psychiatry. 28, 611–616.

    PubMed  CAS  Google Scholar 

  • Woolverton, W.L., Cervo, L. and Johanson, C.E. (1984) Effects of repeated methamphetamine administration on methamphetamine self-administration in rhesus monkeys. Pharmacol Biochem Behav. 21, 737–741.

    Article  PubMed  CAS  Google Scholar 

  • Xu, M., Hu, X.-T., Cooper, D.C, Moratalla, R., Graybiel, A.M., White, F.J. and Tonegawa, S. (1998) Elimination of cocaine-induced hyperactivity and dopamine-mediated neurophysiological effects in dopamine Dj receptor mutant mice. Neuron. 79, 945–955.

    Google Scholar 

  • Xu, M., Moratalla, R., Gold, L.H., Hiroi, N., Koob, G.F., Graybiel, A.M. and Tonegawa, S. (1998) Dopamine Dj receptor mutant mice are deficient in striatal expression of dynorphin and in dopamine-mediated behavioral responses. Neuron. 79, 729–742.

    Google Scholar 

  • Zahm, D.S. and Brog, J.S. (1992) On the significance of sub-territories in the “accumbens” part of the rat ventral striatum. Neuroscience. 50, 751–767.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Unitè de Neurobiologie et Pharmacologic Molèculaire, I’INSERM, Centre Paul Broca, 2ter rue d’Alésia, F-75014, Paris, France

    Pierre Sokoloff, Bernard Le Foll, Sylvie Perachon, Regis Bordet & Jean-Charles Schwartz

  2. Laboratoire de Physiologic, Université René Descartes, Paris, France

    Sophie Ridray

Authors
  1. Pierre Sokoloff
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Bernard Le Foll
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sylvie Perachon
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Regis Bordet
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Sophie Ridray
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jean-Charles Schwartz
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Bernard Le Foll.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sokoloff, P., Foll, B.L., Perachon, S. et al. The dopamine D3 receptor and drug addiction. neurotox res 3, 433–441 (2001). https://doi.org/10.1007/BF03033202

Download citation

  • Received:

  • Revised:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF03033202

Keywords

Search

Navigation