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Nicotinic Acetylcholine Receptors in the Mesolimbic Pathway: Primary Role of Ventral Tegmental Area α6β2* Receptors in Mediating Systemic Nicotine Effects on Dopamine Release, Locomotion, and Reinforcement
Open accessAbstract
α6* nicotinic acetylcholine receptors (nAChRs) are highly and selectively expressed by mesostriatal dopamine (DA) neurons. These neurons are thought to mediate several behavioral effects of nicotine, including locomotion, habit learning, and reinforcement. Yet the functional role of α6* nAChRs in midbrain DA neurons is mostly unknown. The aim of this study was to determine the composition and in vivo functional role of α6* nAChR in mesolimbic DA neurons of male rats. Immunoprecipitation and immunopurification techniques coupled with cell-specific lesions showed that the composition of α6* nAChR in the mesostriatal system is heterogeneous, with (non-α4)α6β2* being predominant in the mesolimbic pathway and α4α6β2* in the nigrostriatal pathway. We verified whether α6* receptors mediate the systemic effects of nicotine on the mesolimbic DA pathway by perfusing the selective antagonists α-conotoxin MII (CntxMII) (α3/α6β2* selective) or α-conotoxin PIA (CntxPIA) (α6β2* selective) into ventral tegmental area (VTA). The intra-VTA perfusion of CntxMII or CntxPIA markedly decreased systemic nicotine-elicited DA release in the nucleus accumbens and habituated locomotion; the intra-VTA perfusion of CntxMII also decreased the rate of nicotine infusion in the maintenance phase of nicotine, but not of food, self-administration. Overall, the results of these experiments show that the α6β2* nAChRs expressed in the VTA are necessary for the effects of systemic nicotine on DA neuron activity and DA-dependent behaviors such as locomotion and reinforcement, and suggest that α6β2*-selective compounds capable of crossing the blood–brain barrier may affect the addictive properties of nicotine and therefore be useful in the treatment of tobacco dependence.
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“Similarly, conotoxins selective for α6/β2 Ã nAChRs disrupt nicotine self-administration in the rat when infused into the VTA (Gotti et al. 2010) and following selfadministration training, these conotoxins decrease the motivation to lever press for nicotine on a progressive ratio schedule (Brunzell et al. 2010).”
From Mechanisms of Nicotine Addiction (2021) · cites this paper as Gotti et al. 2010
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Metadata
- Authors
- Gotti, C., Guiducci, S., Tedesco, V., Corbioli, S., Zanetti, L., Moretti, M., Zanardi, A., Rimondini, R., Mugnaini, M., Clementi, F., Chiamulera, C., & Zoli, M.
- Affiliations
- University of Milan (IT)
- University of Modena and Reggio Emilia (IT)
- University of Verona (IT)
- GlaxoSmithKline (Italy) (IT)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2010-04-14
- Volume
- 30
- Issue
- 15
- Pages
- 5311-5325
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6632743
- OpenAlex
- W2051648601
- Cited by
- 226
- References
- 64
- Citations by year
- 2026: 3 · 2025: 6 · 2024: 7 · 2023: 8 · 2022: 5 · 2021: 3 · 2020: 9 · 2019: 12 · 2018: 10 · 2017: 9 · 2016: 15 · 2015: 21 · 2014: 26 · 2013: 30 · 2012: 29
- FWCI
- 11.99
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- IRIS UNIMORE (University of Modena and Reggio Emilia) (submittedVersion, cc-by-nc-sa)
- Archivio istituzionale della ricerca (Alma Mater Studiorum Università di Bologna) (submittedVersion)
- Funders
- GlaxoSmithKline
- Compagnia di San Paolo
- Fondazione Cariplo
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nicotinic Acetylcholine Receptors Study
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Smoking Behavior and Cessation
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- nicotinic acetylcholine receptors, ventral tegmental area, mesolimbic dopamine system, nicotine, dopamine release, nucleus accumbens, locomotion, nicotine self-administration, nicotine reinforcement, alpha-conotoxin MII, receptor heterogeneity, nicotine dependence, tobacco dependence
- MeSH terms
- Animals, Corpus Striatum, Dopamine, Feeding Behavior, Male, Mesencephalon, Motor Activity, Neural Pathways, Neurons, Nicotine, Nucleus Accumbens, Receptors, Nicotinic, Reinforcement, Psychology, Self Administration, Rats, Sprague-Dawley, Ventral Tegmental Area, Nicotinic Agonists, Nicotinic Antagonists, Conotoxins, Rats
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