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Cited by 242Nicotinic Acetylcholine Receptors StudyNeurotransmitter Receptor Influence on BehaviorSmoking Behavior and Cessation

Effects of nicotine in the dopaminergic system of mice lacking the alpha4 subunit of neuronal nicotinic acetylcholine receptors

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Marubio, L. M., Gardier, A. M., Durier, S., David, D., Klink, R., Arroyo‐Jimenez, M. M., McIntosh, J. M., Rossi, F. +3 more·2003·European Journal of Neuroscience
DOI 10.1046/j.1460-9568.2003.02564.x
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Abstract

The mesostriatal dopaminergic system influences locomotor activity and the reinforcing properties of many drugs of abuse including nicotine. Here we investigate the role of the alpha4 nicotinic acetylcholine receptor (nAChR) subunit in mediating the effects of nicotine in the mesolimbic dopamine system in mice lacking the alpha4 subunit. We show that there are two distinct populations of receptors in the substantia nigra and striatum by using autoradiographic labelling with 125I alpha-conotoxin MII. These receptors are comprised of the alpha4, beta2 and alpha6 nAChR subunits and non-alpha4, beta2, and alpha6 nAChR subunits. Non-alpha4 subunit-containing nAChRs are located on dopaminergic neurons, are functional and respond to nicotine as demonstrated by patch clamp recordings. In vivo microdialysis performed in awake, freely moving mice reveal that mutant mice have basal striatal dopamine levels which are twice as high as those observed in wild-type mice. Despite the fact that both wild-type and alpha4 null mutant mice show a similar increase in dopamine release in response to intrastriatal KCl perfusion, a nicotine-elicited increase in dopamine levels is not observed in mutant mice. Locomotor activity experiments show that there is no difference between wild-type and mutant mice in basal activity in both habituated and non-habituated environments. Interestingly, mutant mice sustain an increase in cocaine-elicited locomotor activity longer than wild-type mice. In addition, mutant mice recover from depressant locomotor activity in response to nicotine at a faster rate. Our results indicate that alpha4-containing nAChRs exert a tonic control on striatal basal dopamine release, which is mediated by a heterogeneous population of nAChRs.

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  • β2* nAChRs are necessary for nicotine self-administration, DA-dependent locomotor activation, nicotine-associated enhancement of NAc DA release, and nicotine-associated enhancement of conditioned reinforcement.

    “Studies in β2* nAChR null mutant mice further show that β2* nAChRs are necessary for nicotine self-administration, DA-dependent locomotor activation, nicotine-associated enhancement of NAc DA release, and nicotine-associated enhancement of conditioned reinforcement (Brunzell et al., 2006; King et al., 2004; Marubio et al., 2003; Picciotto et al., 1998).”

    From It is not “either/or”: Activation and desensitization of nicotinic acetylcholine receptors both contribute to behaviors related to nicotine addiction and mood (2008) · cites this paper as Marubio et al., 2003

  • Mice lacking α4, α6, and/or β2 nAChR subunits do not self-administer nicotine, and restoring these subunits in the ventral tegmental area of knockout mice restores nicotine self-administration.

    “Evidence for this idea stemmed from studies showing that mice lacking the ␣4, ␣6, and/or ␤2 nAChR subunits fail to self-administer nicotine, whereas re-expression of these subunits in the ventral tegmental area of knockout mice restored nicotine self-administration”

    From Varenicline Is a Potent Partial Agonist at α6β2* Nicotinic Acetylcholine Receptors in Rat and Monkey Striatum (2012) · cites this paper as Marubio et al., 2003

  • β2, α4, or α6 nAChR knockout mice fail to self-administer nicotine.

    “extensive studies showing that ␤2, ␣4, or ␣6 nAChRs knockout mice fail to self-administer nicotine (Picciotto et al., 1998;Marubio et al., 2003;Maskos et al., 2005;Pons et al., 2008).”

    From Varenicline Is a Potent Partial Agonist at α6β2* Nicotinic Acetylcholine Receptors in Rat and Monkey Striatum (2012) · cites this paper as Marubio et al., 2003

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Authors
Marubio, L. M., Gardier, A. M., Durier, S., David, D., Klink, R., Arroyo‐Jimenez, M. M., McIntosh, J. M., Rossi, F., Champtiaux, N., Zoli, M., & Changeux, J.
Affiliations
  • Institut Pasteur (FR)
  • Université Paris-Sud (FR)
  • University of Utah (US)
  • University of Modena and Reggio Emilia (IT)
Corresponding author
Marubio, L. M.
ORCID
Venue
European Journal of Neuroscience
Publisher
Wiley
Published
2003-04
Volume
17
Issue
7
Pages
1329-1337
ISSN
  • 0953-816X (ISSN-L)
  • 1460-9568
DOI
10.1046/j.1460-9568.2003.02564.x
OpenAlex
W2011596780
Cited by
242
References
49
Citations by year
2025: 2 · 2024: 2 · 2023: 2 · 2022: 3 · 2021: 2 · 2020: 4 · 2019: 6 · 2018: 5 · 2017: 11 · 2016: 4 · 2015: 13 · 2014: 10 · 2013: 11 · 2012: 15
FWCI
6.43
Type
journal article
Language
en
Open access
Licence
Locations
  • European Journal of Neuroscience (publishedVersion)
  • PubMed (publishedVersion)
  • IRIS UNIMORE (University of Modena and Reggio Emilia) (submittedVersion, cc-by)
Funders
  • National Alliance for Research on Schizophrenia and Depression
  • Ministero dell’Istruzione, dell’Università e della Ricerca
  • Centre National de la Recherche Scientifique
  • National Institutes of Health
  • National Institute of Mental Health (MH53631)
  • National Institute on Drug Abuse (1-P01-DA12661, R01DA012242, P01DA012661, DA12242)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nicotinic Acetylcholine Receptors Study
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
  • Health Sciences › Medicine › Physiology › Smoking Behavior and Cessation
Keywords
nicotine, mesolimbic dopamine system, substantia nigra, striatum, striatal dopamine release, locomotor activity, alpha-conotoxin MII, dopaminergic neurons
MeSH terms
Animals, Autoradiography, Binding Sites, Dopamine, Dose-Response Relationship, Drug, Extracellular Space, Iodine Isotopes, Mice, Inbred C57BL, Motor Activity, Nicotine, Pyridines, Receptors, Nicotinic, Substantia Nigra, Time Factors, Mutagenesis, Neural Networks, Computer, Microdialysis, Ventral Tegmental Area, Mice, Knockout, Patch-Clamp Techniques, Nicotinic Agonists, Bridged Bicyclo Compounds, Heterocyclic, Conotoxins, Mice, In Vitro Techniques

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