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Evidence of long-term expression of behavioral sensitization to both cocaine and ethanol in dopamine transporter knockout mice

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Abstract

Introduction

Locomotor sensitization, defined as the progressive and enduring enhancement of the motor stimulant effects elicited by repeated exposure to drugs of abuse, is the consequence of drug-induced cellular neuroadaptations that likely contribute to addictive behavior. Neuroadaptations within the dopaminergic system have been shown to be involved both in the induction phase and in the long-term expression phase of sensitization upon drug readministration after withdrawal.

Materials and methods

Mice lacking the dopamine transporter (DAT-KO) were used to test the effect of constitutive hyperdopaminergia on the durability of behavioral sensitization to both cocaine and ethanol. The effect of the DAT mutation was simultaneously tested on two inbred genetic backgrounds, C57Bl/6 and DBA/2, chosen for their contrasting addiction-related phenotypes, as well as on the hybrid F1 offspring of a cross between C57Bl/6 and DBA/2 congenic strains.

Results and discussion

In spite of the absence of the DAT, mutant mice were able to develop long-term expression of sensitization to cocaine. Compared to their wild-type littermates, DAT-KO mice exhibited a markedly increased acute ethanol-evoked locomotor activity and developed stronger behavioral sensitization to ethanol during both induction and long-term expression phases. Interestingly, this increased ethanol-induced sensitization was potentiated by the DBA/2 genetic background.

Conclusion

These findings, showing that DAT deletion facilitates sensitization, suggest a cross-sensitization-like effect between genetic- and pharmacological-induced hyperdopaminergia.

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References

  • Belknap JK, Crabbe JC, Riggan J, O’Toole LA (1993) Voluntary consumption of morphine in 15 inbred mouse strains. Psychopharmacology (Berl) 112:352–358

    Article  CAS  Google Scholar 

  • Broadbent J, Kampmueller KM, Koonse SA (2005) Role of dopamine in behavioral sensitization to ethanol in DBA/2J mice. Alcohol 35:137–148

    Article  CAS  PubMed  Google Scholar 

  • 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):1–4

    PubMed  Google Scholar 

  • Crabbe JC, Kosobud A, Young ER, Janowsky JS (1983) Polygenic and single-gene determination of responses to ethanol in BXD/Ty recombinant inbred mouse strains. Neurobehav Toxicol Teratol 5:181–187

    CAS  PubMed  Google Scholar 

  • Crabbe JC, Belknap JK, Buck KJ (1994) Genetic animal models of alcohol and drug abuse. Science 264:1715–1723

    Article  CAS  PubMed  Google Scholar 

  • Crabbe JC, Phillips TJ, Buck KJ, Cunningham CL, Belknap JK (1999) Identifying genes for alcohol and drug sensitivity: recent progress and future directions. Trends Neurosci 22:173–179

    Article  CAS  PubMed  Google Scholar 

  • Cunningham CL (1995) Localization of genes influencing ethanol-induced conditioned place preference and locomotor activity in BXD recombinant inbred mice. Psychopharmacology (Berl) 120:28–41

    Article  CAS  Google Scholar 

  • Cunningham CL, Niehus DR, Malott DH, Prather LK (1992) Genetic differences in the rewarding and activating effects of morphine and ethanol. Psychopharmacology (Berl) 107:385–393

    Article  CAS  Google Scholar 

  • Demarest K, McCaughran J, Mahjubi E, Cipp L, Hitzemann R (1999) Identification of an acute ethanol response quantitative trait locus on mouse chromosome 2. J Neurosci 19:549–561

    CAS  PubMed  Google Scholar 

  • 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 U S A 85:5274–5278

    Article  PubMed  Google Scholar 

  • 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 283:397–401

    Article  CAS  PubMed  Google Scholar 

  • Gainetdinov RR, Mohn AR, Bohn LM, Caron MG (2001) Glutamatergic modulation of hyperactivity in mice lacking the dopamine transporter. Proc Natl Acad Sci U S A 98:11047–11054

    Article  CAS  PubMed  Google Scholar 

  • 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 379:606–612

    Article  CAS  PubMed  Google Scholar 

  • Grimm JW, Hope BT, Wise RA, Shaham Y (2001) Neuroadaptation. Incubation of cocaine craving after withdrawal. Nature 412:141–142

    Article  CAS  PubMed  Google Scholar 

  • Hall FS, Li XF, Randall-Thompson J, Sora I, Murphy DL, Lesch KP, Caron M, Uhl GR (2009) Cocaine-conditioned locomotion in dopamine transporter, norepinephrine transporter and 5-HT transporter knockout mice. Neuroscience 162:870–880

    Article  CAS  PubMed  Google Scholar 

  • 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 U S A 95:4029–4034

    Article  CAS  PubMed  Google Scholar 

  • Jones SR, Gainetdinov RR, Hu XT, Cooper DC, Wightman RM, White FJ, Caron MG (1999) Loss of autoreceptor functions in mice lacking the dopamine transporter. Nat Neurosci 2:649–655

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Kalueff AV, Ren-Patterson RF, Murphy DL (2007) The developing use of heterozygous mutant mouse models in brain monoamine transporter research. Trends Pharmacol Sci 28:122–127

    Article  CAS  PubMed  Google Scholar 

  • Koob GF, Sanna PP, Bloom FE (1998) Neuroscience of addiction. Neuron 21:467–476

    Article  CAS  PubMed  Google Scholar 

  • Lessov CN, Palmer AA, Quick EA, Phillips TJ (2001) Voluntary ethanol drinking in C57BL/6J and DBA/2J mice before and after sensitization to the locomotor stimulant effects of ethanol. Psychopharmacology (Berl) 155:91–99

    Article  CAS  Google Scholar 

  • 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 16:514–520

    Article  PubMed  Google Scholar 

  • Morice E, Denis C, Giros B, Nosten-Bertrand M (2004) Phenotypic expression of the targeted null-mutation in the dopamine transporter gene varies as a function of the genetic background. Eur J Neurosci 20:120–126

    Article  PubMed  Google Scholar 

  • Morice E, Denis C, Macario A, Giros B, Nosten-Bertrand M (2005) Constitutive hyperdopaminergia is functionally associated with reduced behavioral lateralization. Neuropsychopharmacology 30:575–581

    Article  CAS  PubMed  Google Scholar 

  • Morice E, Billard JM, Denis C, Mathieu F, Betancur C, Epelbaum J, Giros B, Nosten-Bertrand M (2007) Parallel loss of hippocampal LTD and cognitive flexibility in a genetic model of hyperdopaminergia. Neuropsychopharmacology 32:2108–2116

    Article  CAS  PubMed  Google Scholar 

  • Phillips TJ, Dickinson S, Burkhart-Kasch S (1994) Behavioral sensitization to drug stimulant effects in C57BL/6J and DBA/2J inbred mice. Behav Neurosci 108:789–803

    Article  CAS  PubMed  Google Scholar 

  • Phillips TJ, Huson M, Gwiazdon C, Burkhart-Kasch S, Shen EH (1995) Effects of acute and repeated ethanol exposures on the locomotor activity of BXD recombinant inbred mice. Alcohol Clin Exp Res 19:269–278

    Article  CAS  PubMed  Google Scholar 

  • Pierce RC, Kalivas PW (1997) A circuitry model of the expression of behavioral sensitization to amphetamine-like psychostimulants. Brain Res Brain Res Rev 25:192–216

    Article  CAS  PubMed  Google Scholar 

  • Robinson TE, Becker JB (1986) Enduring changes in brain and behavior produced by chronic amphetamine administration: a review and evaluation of animal models of amphetamine psychosis. Brain Res 396:157–198

    Article  CAS  PubMed  Google Scholar 

  • Robinson TE, Berridge KC (1993) The neural basis of drug craving: an incentive-sensitization theory of addiction. Brain Res Brain Res Rev 18:247–291

    Article  CAS  PubMed  Google Scholar 

  • Robinson TE, Browman KE, Crombag HS, Badiani A (1998) Modulation of the induction or expression of psychostimulant sensitization by the circumstances surrounding drug administration. Neurosci Biobehav Rev 22:347–354

    Article  CAS  PubMed  Google Scholar 

  • 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 1:132–137 [see comments, published erratum appears in Nat Neurosci 1998 Aug;1(4):330]

    Article  CAS  PubMed  Google Scholar 

  • Shen HW, Hagino Y, Kobayashi H, Shinohara-Tanaka K, Ikeda K, Yamamoto H, Yamamoto T, Lesch KP, Murphy DL, Hall FS, Uhl GR, Sora I (2004) Regional differences in extracellular dopamine and serotonin assessed by in vivo microdialysis in mice lacking dopamine and/or serotonin transporters. Neuropsychopharmacology 29:1790–1799

    Article  CAS  PubMed  Google Scholar 

  • Sora I, Wichems C, Takahashi N, Li XF, Zeng Z, Revay R, Lesch KP, Murphy DL, Uhl GR (1998) Cocaine reward models: conditioned place preference can be established in dopamine- and in serotonin-transporter knockout mice. Proc Natl Acad Sci U S A 95:7699–7704

    Article  CAS  PubMed  Google Scholar 

  • 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 U S A 98:5300–5305

    Article  CAS  PubMed  Google Scholar 

  • Spielewoy C, Biala G, Roubert C, Hamon M, Betancur C, Giros B (2001) Hypolocomotor effects of acute and daily d-amphetamine in mice lacking the dopamine transporter. Psychopharmacology (Berl) 159:2–9

    Article  CAS  Google Scholar 

  • Thomsen M, Hall FS, Uhl GR, Caine SB (2009) Dramatically decreased cocaine self-administration in dopamine but not serotonin transporter knock-out mice. J Neurosci 29:1087–1092

    Article  CAS  PubMed  Google Scholar 

  • Vanderschuren LJ, Kalivas PW (2000) Alterations in dopaminergic and glutamatergic transmission in the induction and expression of behavioral sensitization: a critical review of preclinical studies. Psychopharmacology (Berl) 151:99–120

    Article  CAS  Google Scholar 

  • Vengeliene V, Bilbao A, Molander A, Spanagel R (2008) Neuropharmacology of alcohol addiction. Br J Pharmacol 154:299–315

    Article  CAS  PubMed  Google Scholar 

  • Weiss S, Tzavara ET, Davis RJ, Nomikos GG, Michael McIntosh J, Giros B, Martres MP (2007) Functional alterations of nicotinic neurotransmission in dopamine transporter knock-out mice. Neuropharmacology 52:1496–1508

    Article  CAS  PubMed  Google Scholar 

  • Wise RA (1998) Drug-activation of brain reward pathways. Drug Alcohol Depend 51:13–22

    Article  CAS  PubMed  Google Scholar 

  • Wise RA, Bozarth MA (1987) A psychomotor stimulant theory of addiction. Psychol Rev 94:469–492

    Article  CAS  PubMed  Google Scholar 

  • Yao WD, Gainetdinov RR, Arbuckle MI, Sotnikova TD, Cyr M, Beaulieu JM, Torres GE, Grant SG, Caron MG (2004) Identification of PSD-95 as a regulator of dopamine-mediated synaptic and behavioral plasticity. Neuron 41:625–638

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We are grateful to Drs. Catalina Betancur and Marie-Pascale Martres for helpful comments on the manuscript. We thank Philippe Chevalier (in memoriam) and Laurent Hillard for animal care. This work was supported by INSERM, Action Thématique Concertée (ATC) Alcool, and the Fondation pour la Recherche Médicale. EM was supported by a fellowship from the Ministère de l’Eduction Nationale, de la Recherche et de la Technologie.

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Author notes

  1. Cécile Denis

    Present address: I-Stem, INSERM-U861 Genethon, 1 ru e de l’Internationale, BP 118, 91004, Evry, France

Authors and Affiliations

  1. Institut National de la Santé et de la Recherche Médicale (INSERM), U952, 9 quai Saint Bernard, 75005, Paris, France

    Elise Morice, Cécile Denis, Bruno Giros & Marika Nosten-Bertrand

  2. Centre National de la Recherche Scientifique (CNRS), UMR 7224, 9 quai Saint Bernard, 75005, Paris, France

    Elise Morice, Cécile Denis, Bruno Giros & Marika Nosten-Bertrand

  3. Université Pierre et Marie Curie (UMPC) Paris 06, 9 quai Saint Bernard, 75005, Paris, France

    Elise Morice, Cécile Denis, Bruno Giros & Marika Nosten-Bertrand

  4. Douglas Hospital Research Center, Department of Psychiatry, McGill University, Montreal, QC, Canada

    Bruno Giros

  5. INSERM UMRS-952 CNRS UMR 7224, Physiopathologie des Maladies du Système nerveux Central, UPMC, Bât B 4ème étage, 9 quai Saint Bernard, case courrier 37, 75252, Paris Cedex 05, France

    Bruno Giros & Marika Nosten-Bertrand

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  1. Elise Morice
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Correspondence to Bruno Giros or Marika Nosten-Bertrand.

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Morice, E., Denis, C., Giros, B. et al. Evidence of long-term expression of behavioral sensitization to both cocaine and ethanol in dopamine transporter knockout mice. Psychopharmacology 208, 57–66 (2010). https://doi.org/10.1007/s00213-009-1707-0

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  • DOI: https://doi.org/10.1007/s00213-009-1707-0

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