Hostname: page-component-cd9895bd7-fscjk Total loading time: 0 Render date: 2024-12-26T13:01:14.207Z Has data issue: false hasContentIssue false
  • English
  • Français

Dopamine D3 receptor agents as potential new medications for drug addiction

Published online by Cambridge University Press:  16 April 2020

B. Le Foll ,
J.C. Schwartz  and
P. Sokoloff
B. Le Foll*
Affiliation:
Unité de neurobiologie et pharmacologie moléculaire de l'Inserm, Centre Paul Broca, 75014Paris, France
J.C. Schwartz
Affiliation:
Unité de neurobiologie et pharmacologie moléculaire de l'Inserm, Centre Paul Broca, 75014Paris, France
P. Sokoloff
Affiliation:
Unité de neurobiologie et pharmacologie moléculaire de l'Inserm, Centre Paul Broca, 75014Paris, France
*
*Correspondence and reprints: Bernard Le Foll, Unité de Neurobiologie et Pharmacologie Moléculaire de l'INSERM, Centre Paul Broca, 2ter rue d'Alésia, F-75014 Paris, France
Get access

Summary

All drugs abused by humans increase dopamine in the shell of nucleus accumbens, which implicate the neurons of this structure in their hedonic and reinforcing properties. Among the various dopamine receptor subtypes, the D1 (D1R) and D3 (D3R) receptors co-localise in accumbal shell neurons. Synergistic D1R/D3R interactions at this level were found on gene expression and during induction and expression of behavioral sensitisation to levodopa in rats bearing unilateral lesions of dopamine neurons. Behavioral sensitisation to abused drugs is a component of their long-term effects. Converging pharmacologic, human postmortem and genetic studies suggest the involvement of the D3R in reinforcing effects of drugs; D3R agonists reduced cocaine self-administration in rats, without disrupting the maintenance of self-administration. These data suggest the use of D3R agonists as partial substitutes to treat cocaine dependence, by affecting its reward component. However, substitution therapies maintain dependence and may be inefficient on drug craving and relapse, which are the unsolved and critical problems in the treatment of drug addiction. Recently, a highly selective and partial D3R agonist was shown to reduce cocaine-associated cue-controlled behaviour in rats, without having any primary intrinsic effects. As drug-associated cues maintain drug-seeking in animals and elicit craving and relapse in humans, such D3R agents have potential therapeutic applications.

Keywords

behavioral sensitisationcocainedrug-associated cuesnucleus accumbens shellsynergism
Type
Original Article
Information
European Psychiatry , Volume 15 , Issue 2 , March 2000 , pp. 140 - 146
Copyright
Copyright © Éditions scientifiques et médicales Elsevier SAS 2000

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Altman, JEveritt, B.JGlautier, SMarkou, ANutt, DOretti, R et al. The biological, social and clinical bases of drug addiction: commentary and debate. Psychopharmacology (Berl) 125 1996 285–345CrossRefGoogle ScholarPubMed
Arroyo, MMarkou, ARobbins, T.WEveritt, B.JAcquisition, 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 1999 331–344CrossRefGoogle Scholar
Bordet, RRidray, SCarboni, SDiaz, JSokoloff, PSchwartz, J.CInduction of dopamine D3 receptor expression as a mechanism of behavioral sensitization to levodopa. Proc Natl Acad Sci USA 94 1997 3363–3367CrossRefGoogle Scholar
Bouthenet, M.LSouil, EMartres, M.PSokoloff, PGiros, BSchwartz, J.CLocalization of dopamine D3 receptor mRNA in the rat brain using in situ hybridization histochemistry: comparison with D2 receptor mRNA. Brain Res 564 1991 203–219CrossRefGoogle ScholarPubMed
Cabib, SCastellano, CCestari, VFilibeck, UPuglisi-Allegra, SD1 and D2 receptor antagonists differently affect cocaine-induced locomotor hyperactivity in the mouse. Psychopharmacology (Berl) 105 1991 335–339CrossRefGoogle ScholarPubMed
Caine, S.BKoob, G.FModulation of cocaine self-administration in the rat through D3 dopamine receptors. Science 260 1993 1814–1816CrossRefGoogle Scholar
Caine, S.BKoob, G.FEffects of dopamine D-1 and D-2 antagonists on cocaine self-administration under different schedules of reinforcement in the rat. J Pharmacol Exp Ther 270 1994 209–218Google ScholarPubMed
Caine, S.BKoob, G.FPretreatment with the dopamine agonist 7-OH-DPAT shifts the cocaine self-administration dose-effect function to the left under different schedules in the rat. Behav Pharmacol 6 1995 333–347CrossRefGoogle ScholarPubMed
Caine, S.BKoob, G.FParsons, L.HEveritt, B.JSchwartz, J.CSokoloff, PD3 receptor test in vitro predicts decreased cocaine self-administration in rats. Neuroreport 8 1997 2373–2377CrossRefGoogle ScholarPubMed
Childress, E.RRoohsenow, D.JRobbins, S.HO'Brien, C.PClassically conditioned factors in drug dependence.Lowinson, WLuiz, PMillman, R.BLangard, J.GSubstance abuse: a comprehensive text book. 1992 Baltimore: Williams and Wilkins 56–69Google Scholar
Cole, R.LKonradi, CDouglass, JHyman, S.ENeuronal adaptation to amphetamine and dopamine: molecular mechanisms of prodynorphin gene regulation in rat striatum. Neuron 14 1995 813–823CrossRefGoogle ScholarPubMed
DeWit, HStewart, JReinstatement of cocaine-reinforced responding in the rat. Psychopharmacol 75 1981 134–143CrossRefGoogle Scholar
DiChiara, GImperato, ADrugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats. Proc Natl Acad Sci USA 85 1988 5274–5278CrossRefGoogle Scholar
Diaz, JLévesque, DLammers, C.HGriffon, NMartres, M.PSchwartz, J.C et al. Phenotypical characterization of neurons expressing the dopamine D3 receptor. Neuroscience 65 1995 731–745CrossRefGoogle ScholarPubMed
Duaux, EGorwood, PSautel, FGriffon, NSokoloff, PSchwartz, J.C et al. Homozygosity at the dopamine D3 receptor gene is associated with opioid dependence. Mol Psychiatry 3 1998 333–336CrossRefGoogle Scholar
Gawin, F.WCocaine addiction: psychology and neurophysiology. Science 251 1991 1580–1586CrossRefGoogle ScholarPubMed
Grech, D.MSpealman, R.DBergman, JSelf-administration of D1 receptor agonists by squirrel monkeys. Psychopharmacol 125 1996 97–104CrossRefGoogle ScholarPubMed
Griffon, NPilon, CSautel, FSchwartz, J.CSokoloff, PTwo intracellular pathways for the dopamine D3 receptor: opposite and synergistic interactions with cyclic AMP. J Neurochem 67 1997 1–9Google Scholar
Heimer, LZham, D.SAlheid, G.FBasal ganglia.Paxinos, GThe rat nervous system. 1995 New York: Academic Press 579–628Google Scholar
Horger, B.AShelton, KSchenk, SPreexposure sensitizes rats to the rewarding effects of cocaine. Pharmacol Biochem Behav 37 1990 707–711CrossRefGoogle ScholarPubMed
Kalivas, P.WStewart, JDopamine transmission in the initition and expression of drug- and stress-induced sensitization of motor activity. Brain Res Rev 16 1991 223–244CrossRefGoogle Scholar
Koob, G.FDopamine, addiction and reward. Sem Neurosci 4 1992 139–148CrossRefGoogle Scholar
Krebs, M.OSautel, FBourdel, M.CSokoloff, PSchwartz, J.COlié, J.P et al. Dopamine D3 receptor gene variants and substance abuse in schizophrenia. Mol Psychiatry 3 1998 337–341CrossRefGoogle Scholar
Lamas, XNegus, S.SNader, M.AMello, N.KEffects of putative dopamine D3 receptor agonist 7-OH-DPAT in rhesus monkeys trained to discriminate cocaine from saline. Psychopharmacology (Berl) 124 1996 306–314CrossRefGoogle ScholarPubMed
Lett, B.TRepeated exposures intensify rather than diminish the rewarding effects of amphetamine, morphine, and cocaine. Psychopharmacol 98 1989 357–362CrossRefGoogle ScholarPubMed
Lévesque, DDiaz, JPilon, CMartres, M.PGiros, BSouil, E et al. 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 1992 8155–8159CrossRefGoogle ScholarPubMed
Lévesque, DMartres, M.PDiaz, JGriffon, NLammers, C.HSokoloff, P et al. 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 1995 1719–1723CrossRefGoogle ScholarPubMed
Maldonado, RRobledo, PChover, A.JCaine, S.BKoob, G.FD1 dopamine receptors in the nucleus accumbens modulate cocaine self-administration in the rat. Pharmacol Biochem Behav 45 1993 239–242CrossRefGoogle ScholarPubMed
Meil, W.MSee, R.EConditioned cue recovery of responding following prolonged withdrawal from self-administered cocaine in rats: an animal model of relapse. Behav Pharmacol 7 1996 754–763Google Scholar
Meil, W.MSee, R.ELesions of the basolateral amygdala abolish the ability of drug-associated cues to reinstate responding during withdrawal from self-administered cocaine. Behav Brain Res 87 1997 139–148CrossRefGoogle ScholarPubMed
Milner, P.MBrain-stimulation reward: a review. Can J Psychol 45 1991 1–36CrossRefGoogle ScholarPubMed
Nestler, E.JMolecular mechanisms of drug addiction. J Neurosci 12 1992 2439–2450CrossRefGoogle ScholarPubMed
O'Brien, C.PChildress, A.RMcMellan, A.TEhrman, R.AA learning model of addiction. Res Publ Assoc Res Nerv Ment Dis 70 1992 157–177Google Scholar
O'Brien, C.PMcMellan, A.TMyths about the treatment of addiction. Lancet 347 1996 237–240CrossRefGoogle Scholar
Pennartz, C.MGroenewegen, H.JLopes, D.ASilva, F.HThe nucleus accumbens as a complex of functionally distinct neuronal ensembles: an integration of behavioural, electrophysiological and anatomical data. Prog Neurobiol 42 1994 719–761CrossRefGoogle ScholarPubMed
Pilla, MPerachon, SSautel, FGarrido, FMann, AWermuth, C.G et al. Selective inhibition of cocaine-seeking behaviour by a partial dopamine D3 receptor agonist. Nature 400 1999 371–375CrossRefGoogle ScholarPubMed
Pulverenti, LKoob, G.FDopamine agonists, partial agonists and psychostimulant addiction. Trends Pharmacol Sci 15 1994 374–379CrossRefGoogle Scholar
Ridray, SGriffon, NSouil, EMignon, VCarboni, SDiaz, J et al. Coexpression of dopamine D1 and D3 receptors in rat ventral striatum: opposite and synergistic functional interactions. Eur J Neurosci 10 1998 1676–1686CrossRefGoogle ScholarPubMed
Segal, D.MMoraes, C.TMash, D.CUp-regulation of D3 dopamine receptor mRNA in the nucleus accumbens of human cocaine fatalities. Mol Brain Res 45 1997 335–339CrossRefGoogle ScholarPubMed
Self, D.WNestler, E.JRelapse to drug-seeking: neural and molecular mechanisms. Drug Alcohol Dep 51 1988 49–60CrossRefGoogle Scholar
Sokoloff, PGiros, BMartres, M.PBouthenet, M.LSchwartz, J.CMolecular cloning and characterization of a novel dopamine receptor (D3) as a target for neuroleptics. Nature 347 1990 146–151CrossRefGoogle ScholarPubMed
Spealman, R.DDopamine D3 receptor agonists partially reproduce the discriminative stimulus effects of cocaine in squirrel monkeys. J Pharmacol Exp Ther 278 1996 1128–1137Google ScholarPubMed
Spealman, R.DBergman, JMadras, B.KMelia, K.FDiscriminative stimulus effects of cocaine in squirrel monkeys: involvement of dopamine receptor subtypes. J Pharmacol Exp Ther 258 1991 945–953Google ScholarPubMed
Staley, J.KMash, D.CAdaptive increase in D3 dopamine receptors in the brain reward circuits of human cocaine fatalities. J Neurosci 16 1996 6100–6106CrossRefGoogle ScholarPubMed
Stewart, JConditioned and unconditioned drug effects in relapse to opiate and stimulant drug-administration. Prog Neuropsychopharmacol Biol Psychiatry 7 1983 591–597CrossRefGoogle Scholar
Tella, S.RDifferential blockade of chronic versus acute effects of intravenous cocaine by dopamine receptor antagonists. Pharmacol Biochem Behav 48 1994 151–159CrossRefGoogle ScholarPubMed
Wilker, ADynamics of drug dependence. Arch Gen Psychiatry 28 1973 611–616Google Scholar
Woolverton, W.LCervo, LJohanson, C.EEffects of repeated methamphetamine administration on methamphetamine self-administration in rhesus monkeys. Pharmacol Biochem Behav 21 1984 737–741CrossRefGoogle ScholarPubMed
Zahm, D.SBrog, J.SOn the significance of subterritories in the ‘accumbens’ part of the rat ventral striatum. Neuroscience 50 1992 751–767CrossRefGoogle ScholarPubMed
Submit a response

Comments

No Comments have been published for this article.