Skip to main content

Advertisement

SpringerLink
Log in

Genetic dissociation of two behaviors associated with nicotine addiction: Beta-2 containing nicotinic receptors are involved in nicotine reinforcement but not in withdrawal syndrome

  • Original Investigation
  • Published:
Psychopharmacology Aims and scope Submit manuscript

Abstract

Rationale

Nicotine addiction is characterized by two distinct behaviors, chronic compulsive self-administration and the induction of a withdrawal syndrome upon cessation of nicotine consumption.

Objective

To examine if these two processes rely on β2-containing nicotinic receptors—β2*nAChRs—we analyzed the behavior of mice lacking these receptors in the two situations.

Results

First, we showed that, in contrast to wild-type (WT) mice, β2-knockout (β2−/−) mice exhibit no intra-ventral tegmental area (VTA) nicotine self-administration, whereas their ability to self-administer morphine is intact. However, β2−/− mice showed some sensitivity to locomotor effects of nicotine, implying an effect of the drug on other nicotinic subtypes. Then, we observed that β2−/− mice exhibited a normal nicotine withdrawal syndrome, i.e., increased levels of rearing and jumping upon precipitated withdrawal. Thus, the β2*nAChRs are not involved in the behaviors induced by cessation of nicotine consumption.

Conclusion

Taken together, the present data demonstrated a genetic dissociation of two distinct behavioral patterns associated with nicotine addiction. They further suggested that independent molecular mechanisms underlie these two aspects, offering the possibility of controlling them separately.

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

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  • Aghajanian GK (1978) Tolerance of locus coeruleus neurones to morphine and suppression of withdrawal response by clonidine. Nature 276:186–188

    Article  PubMed  CAS  Google Scholar 

  • Aston-Jones G, Harris GC (2004) Brain substrates for increased drug seeking during protracted withdrawal. Neuropharmacology 47:167–179

    Article  PubMed  CAS  Google Scholar 

  • Barik J, Wonnacott S (2005) Indirect modulation by {alpha}7 nicotinic acetylcholine receptors of noradrenaline release in rat hippocampal slices: interaction with glutamate and GABA systems and effect of nicotine withdrawal. Mol Pharmacol 69:618–628

    Article  PubMed  CAS  Google Scholar 

  • Bozarth MA, Wise RA (1984) Anatomically distinct opiate receptor fields mediate reward and physical dependence. Science 224:516–517

    Article  PubMed  CAS  Google Scholar 

  • Castane A, Valjent E, Ledent C, Parmentier M, Maldonado R, Valverde O (2002) Lack of CB1 cannabinoid receptors modifies nicotine behavioral responses, but not nicotine abstinence. Neuropharmacology 43:857–867

    Article  PubMed  CAS  Google Scholar 

  • Cook MR, Gerkovich MM, Graham C, Hoffman SJ, Peterson RC (2003) Effects of the nicotine patch on performance during the first week of smoking cessation. Nicotine Tob Res 5:169–180

    Article  PubMed  CAS  Google Scholar 

  • Cormier A, Paas Y, Zini R, Tillement JP, Lagrue G, Changeux JP, Grailhe R (2004) Long-term exposure to nicotine modulates the level and activity of acetylcholine receptors in white blood cells of smokers and model mice. Mol Pharmacol 66:1712–1718

    Article  PubMed  CAS  Google Scholar 

  • Corrigall WA (1991) Understanding brain mechanisms in nicotine reinforcement. Br J Addict 86:507–510

    Article  PubMed  CAS  Google Scholar 

  • Corrigall WA, Coen KM, Adamson KL (1994) Self-administered nicotine activates the mesolimbic dopamine system through the ventral tegmental area. Brain Res 653:278–284

    Article  PubMed  CAS  Google Scholar 

  • Corrigall WA, Coen KM, Zhang J, Adamson KL (2001) GABA mechanisms in the pedunculopontine tegmental nucleus influence particular aspects of nicotine self-administration selectively in the rat. Pyschopharmacology 158:190–197

    Article  CAS  Google Scholar 

  • Corrigall WA, Coen KM, Zhang J, Adamson KL (2002) Pharmacological manipulations of the pedunculopontine tegmental nucleus in the rat reduce self-administration of both nicotine and cocaine. Pyschopharmacology 160:198–205

    Article  CAS  Google Scholar 

  • Cryan JF, Gasparini F, van Heeke G, Markou A (2003) Non-nicotinic neuropharmacological strategies for nicotine dependence: beyond buproprion. Drug Discov Today 8:1025–1034

    Article  PubMed  CAS  Google Scholar 

  • Damaj MI, Kao W, Martin BR (2003) Character of spontaneous and precipitated nicotine withdrawal in the mouse. J Pharmacol Exp Ther 307:526–534

    Article  PubMed  CAS  Google Scholar 

  • David V, Cazala P (1994) Differentiation of intracranial morphine self-administration behaviour among five brain regions in mice. Pharmacol Biochem Behav 48:625–633

    Article  PubMed  CAS  Google Scholar 

  • David V, Durkin TP, Cazala P (2002) Differential effects of the dopamine D2/D3 receptor antagonist sulpiride on self-administration of morphine into the ventral tegmental area or the nucleus accumbens. Psychopharmacology 160:307–317

    Article  PubMed  CAS  Google Scholar 

  • David V, Segu L, Buhot MC, Ichaye M, Cazala P (2004) Rewarding effects elicited by cocaine microinjections into the ventral tegmental area of C57BL/6 mice: involvement of dopamine D1 and serotonin 1B receptors. Psychopharmacology 174:367–375

    Article  PubMed  CAS  Google Scholar 

  • David V, Besson M, Changeux JP, Granon S, Cazala P (2006) Reinforcing effects of nicotine microinjections into the ventral tegmental area of mice: dependence on cholinergic nicotinic and dopaminergic D1 receptors. Neuropharmacology (in press)

  • Di Chiara G (2000) Role of dopamine in the behavioural actions of nicotine related to addicition. Eur J Pharmacol 393:295–314

    Article  PubMed  Google Scholar 

  • Epping-Jordan MP, Watkins SS, Koob GF, Markou A (1998) Dramatic decrease in brain reward function during nicotine withdrawal. Nature 393:76–79

    Article  PubMed  CAS  Google Scholar 

  • Frenois F, Cador M, Caille S, Stinus L, Le Moine C (2002) Neural correlates of the motivational and somatic components of naloxone-precipitated morphine withdrawal. Eur J Neurosci 16:1377–1389

    Article  PubMed  Google Scholar 

  • Fung YK, Schmid M, Anderson TM, Lau YS (1996) Effects of nicotine withdrawal on central dopaminergic systems. Pharmacol Biochem Behav 53:635–640

    Article  PubMed  CAS  Google Scholar 

  • Grabus SD, Martin BR, Damaj MI (2005) Physical dependence in the mouse: involvement of Alpha7 nicotinic receptor subtype. Eur J Pharmacol 515:90–93

    Article  PubMed  CAS  Google Scholar 

  • Granon S, Faure P, Changeux JP (2003) Executive and social behaviors under nicotinic receptor regulation. Proc Natl Acad Sci U S A 100:9596–9601

    Article  PubMed  CAS  Google Scholar 

  • Harlan RE, Garcia MM (1998) Drugs of abuse and immediate-early genes in the forebrain. Mol Neurobiol 16:221–267

    Article  PubMed  CAS  Google Scholar 

  • Higgins GA, Sellers EM (1994) Antagonist-precipitated opioid withdrawal in rats: evidence for dissociations between physical and motivational signs. Pharmacol Biochem Behav 48:1–8

    Article  PubMed  CAS  Google Scholar 

  • Hildebrand BE, Nomikos GG, Bondjers C, Nisell M, Svensson TH (1997) Behavioral manifestations of the nicotine abstinence syndrome in the rat: peripheral versus central mechanisms. Psychopharmacology 129:348–356

    Article  PubMed  CAS  Google Scholar 

  • Hill JA Jr, Zoli M, Bourgeois JP, Changeux JP (1993) Immunocytochemical localization of a neuronal nicotinic receptor: the beta2-subunit. J Neurosci 13:1551–1568

    PubMed  CAS  Google Scholar 

  • Isola R, Vogelsberg V, Wemlinger TA, Neff H, Hadjiconstantinou M (1999) Nicotine abstinence in the mouse. Brain Res 850:189–196

    Article  PubMed  CAS  Google Scholar 

  • Kenny PJ, Markou A (2001) Neurobiology of the nicotine withdrawal syndrome. Pharmacol Biochem Behav 70:531–549

    Article  PubMed  CAS  Google Scholar 

  • Klink R, de Kerchove d’Exaerde A, Zoli M, Changeux JP (2001) Molecular and physiological diversity of nicotinic acetylcholine receptors in the midbrain dopaminergic nuclei. J Neurosci 21:1452–1463

    PubMed  CAS  Google Scholar 

  • Laviolette SR, van der Kooy D (2004) The neurobiology of nicotine addiction: bridging the gap from molecules to behaviour. Nature Rev Neurosci 5:55–65

    Article  CAS  Google Scholar 

  • Maldonado R, Stinus L, Gold LH, Koob GF (1992) Role of different brain structures in the expression of the physical morphine withdrawal syndrome. J Pharmacol Exp Ther 261:669–677

    PubMed  CAS  Google Scholar 

  • Martellotta MC, Kuzmin A, Zvartau E, Cossu G, Gessa GL, Fratta W (1995) Isradipine inhibits nicotine intravenous self-administration in drug-naive mice. Pharmacol Biochem Behav 52:271–274

    Article  PubMed  CAS  Google Scholar 

  • Maskos U, Molles BE, Pons S, Besson M, Guiard BP, Guilloux JP, Evrard A, Cazala P, Cormier A, Mameli-Engvall M, Dufour N, Cloez-Tayarani I, Bemelmans AP, Mallet J, Gardier AM, David V, Faure P, Granon S, Changeux JP (2005) Nicotine reinforcement and cognition restored by targeted expression of nicotinic receptors. Nature 436:103–107

    Article  PubMed  CAS  Google Scholar 

  • McBride WJ, Murphy JM, Ikemoto S (1999) Localization of brain reinforcement mechanisms: intracranial self-administration and intracranial place-conditioning studies. Behav Brain Res 101:129–152

    Article  PubMed  CAS  Google Scholar 

  • Motoshima S, Suemaru K, Kawasaki Y, Jin C, Kawasaki H, Gomita Y, Araki H (2005) Effects of alpha4beta2 and alpha7 nicotinic acetylcholine receptor antagonists on place aversion induced by naloxone in single-dose morphine-treated rats. Eur J Pharmacol 519:91–95

    Article  PubMed  CAS  Google Scholar 

  • Mucha RF (1987) Is the motivational effect of opiate withdrawal reflected by common somatic indices of precipitated withdrawal? A place conditioning study in the rat. Brain Res 418:214–220

    Article  PubMed  CAS  Google Scholar 

  • Nomikos GG, Schilstrom B, Hildebrand BE, Panagis G, Grenhoff J, Svensson TH (2000) Role of alpha7 nicotinic receptors in nicotine dependence and implications for psychiatric illness. Behav Brain Res 113:97–103

    Article  PubMed  CAS  Google Scholar 

  • Paxinos G, Franklin KBJ (2004) The mouse brain in stereotaxic coordinates. Academic Press, Elsevier Science, San Diego, USA

    Google Scholar 

  • Picciotto MR, Corrigall WA (2002) Neuronal systems underlying behaviors related to nicotine addiction: neural circuits and molecular genetics. J Neurosci 22:3338–3341

    PubMed  CAS  Google Scholar 

  • Picciotto MR, Zoli M, Lena C, Bessis A, Lallemand Y, Le Novère N, Vincent P, Pich EM, Brulet P, Changeux JP (1995) Abnormal avoidance learning in mice lacking functional high-affinity nicotine receptor in the brain. Nature 374:65–67

    Article  PubMed  CAS  Google Scholar 

  • Picciotto MR, Zoli M, Rimondini R, Lena C, Marubio LM, Pich EM, Fuxe K, Changeux JP (1998) Acetylcholine receptors containing the beta2 subunit are involved in the reinforcing properties of nicotine. Nature 391:173–177

    Article  PubMed  CAS  Google Scholar 

  • Pidoplichko VI, DeBiasi M, Williams JT, Dani JA (1997) Nicotine activates and desensitizes midbrain dopamine neurons. Nature 390:401–404

    Article  PubMed  CAS  Google Scholar 

  • Rasmussen T, Swedberg DB (1998) Reinforcing effects of nicotinic compounds: intravenous self-administration in drug-naive mice. Pharmacol Biochem Behav 60:567–573

    Article  PubMed  CAS  Google Scholar 

  • Rose JE, Corrigall WA (1997) Nicotine self-administration in animals and humans: similarities and differences. Psychopharmacology 130:28–40

    Article  PubMed  CAS  Google Scholar 

  • Russell MA, Jarvis M, Iyer R, Feyerabend C (1980) Relation of nicotine yield of cigarettes to blood nicotine concentrations in smokers. Br Med J 280:972–976

    Article  PubMed  CAS  Google Scholar 

  • Salas R, Pieri F, De Biasi M (2004) Decreased signs of nicotine withdrawal in mice null for the beta4 nicotinic acetylcholine receptor subunit. J Neurosci 24:10035–10039

    Article  PubMed  CAS  Google Scholar 

  • Salmon AM, Evrard A, Damaj I, Changeux JP (2004) Reduction of withdrawal signs after chronic exposure of alpha-calcitonin gene-related peptide knock-out mice. Neurosci Lett 360:73–76

    Article  PubMed  CAS  Google Scholar 

  • Shoaib M, Gommans J, Morley A, Stolerman IP, Grailhe R, Changeux JP (2002) The role of nicotinic receptor beta-2 subunits in nicotine discrimination and conditioned taste aversion. Neuropharmacology 42:530–539

    Article  PubMed  CAS  Google Scholar 

  • Stolerman IP, Jarvis MJ (1995) The scientific case that nicotine is addictive. Psychopharmacology 117:2–10

    Article  PubMed  CAS  Google Scholar 

  • Volkow ND, Fowler JS, Wang GJ (2004) The addicted human brain viewed in the light of imaging studies: brain circuits and treatment strategies. Neuropharmacology 47:3–13

    Article  PubMed  CAS  Google Scholar 

  • Wise RA, Hoffman DC (1992) Localization of drug reward mechanisms by intracranial injections. Synapse 10:247–263

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

This research was supported by the Institut Pasteur, the CNRS and the Collège de France. MB is supported by a Ph.D. grant from the Letten F. Saugstad Foundation. SS is supported by a post-doc grant from the “Association pour la Recherche sur les Nicotianés”. The authors thank A.-M. Salmon for her help in designing pilot withdrawal experiments.

Author information

Authors and Affiliations

  1. Unité CNRS 2182 “Récepteurs & Cognition”, Département de Neuroscience, Institut Pasteur, 25 rue du Dr. Roux, 75015, Paris, France

    M. Besson, S. Suarez, A. Cormier, J.-P. Changeux & S. Granon

  2. Laboratoire de Neurosciences Cognitives, CNRS UMR 5106, Université de Bordeaux I, Talence, France

    V. David & P. Cazala

Authors
  1. M. Besson
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. V. David
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. S. Suarez
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. A. Cormier
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. P. Cazala
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. J.-P. Changeux
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. S. Granon
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to S. Granon.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Besson, M., David, V., Suarez, S. et al. Genetic dissociation of two behaviors associated with nicotine addiction: Beta-2 containing nicotinic receptors are involved in nicotine reinforcement but not in withdrawal syndrome. Psychopharmacology 187, 189–199 (2006). https://doi.org/10.1007/s00213-006-0418-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-006-0418-z

Keywords

Search

Navigation