Chronic Nicotine Differentially Regulates α6- and β3-Containing Nicotinic Cholinergic Receptors in Rat Brain
Abstract
We investigated the effects of chronic nicotine on alpha6- and beta3-containing nicotinic acetylcholine receptors (nAChRs) in two rat brain regions using three methodological approaches: radioligand binding, immunoprecipitation, and nicotine-stimulated synaptosomal release of dopamine. Nicotine was administered by osmotic minipumps for 2 weeks. Quantitative autoradiography with [(125)I]alpha-conotoxin MII to selectively label alpha6(*) nAChRs showed a 28% decrease in binding in the striatum but no change in the superior colliculus. Immunoprecipitation of nAChRs labeled by [(3)H]epibatidine in these two regions showed that chronic nicotine increased alpha4- and beta2-containing nAChRs by 39 to 67%. In contrast, chronic nicotine caused a 39% decrease in alpha6-containing nAChRs in striatum but no change in superior colliculus. No changes in beta3-containing nAChRs were seen in either region after chronic nicotine. The decreased expression of alpha6-containing nAChRs persisted for at least 3 days, recovering to baseline by 7 days after removal of the pumps. There was a small but significant decrease in total nicotine-stimulated dopamine release in striatal synaptosomes after nicotine exposure. However, the component of dopamine release that was resistant to alpha-conotoxin MII blockade was unaffected, whereas dopamine release that was sensitive to blockade by alpha-conotoxin MII was decreased by 56%. These findings indicate that the alpha6(*) nAChR is regulated differently from other nAChR subtypes, and they suggest that the inclusion of a beta3 subunit with alpha6 may serve to inhibit nicotine-induced down-regulation of these receptors.
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β3 effects on receptor trafficking and upregulation may explain why striatal α6-containing receptors without β3 are downregulated by nicotine while those with β3 are unaffected.
“The effects of β3 on receptor trafficking and upregulation may help explain why in the striatum α6-containing receptors without β3 are downregulated by nicotine, while those containing β3 are unaffected (Perry et al. 2007).”
From Nicotine Withdrawal (2015) · cites this paper as Perry et al. 2007
Different brain regions and nAChR subtypes have different upregulation parameters.
“While this prediction is straightforward, testing it has been confounded by the observation that different brain regions and nAChR subtypes have different upregulation parameters (Collins et al., 1989; Mao et al., 2008; Perry et al., 2007) and a lack of understanding of which brain regions are critically involved in specific withdrawal symptoms.”
From The duration of nicotine withdrawal-associated deficits in contextual fear conditioning parallels changes in hippocampal high affinity nicotinic acetylcholine receptor upregulation (2012) · cites this paper as Perry et al., 2007
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- Authors
- Perry, D. C., Mao, D., Gold, A. B., McIntosh, J. M., Pezzullo, J. C., & Kellar, K. J.
- Affiliations
- George Washington University (US)
- Georgetown University (US)
- Venue
- The Journal of Pharmacology and Experimental Therapeutics
- Publisher
- Elsevier BV
- Published
- 2007-07
- Volume
- 322
- Issue
- 1
- Pages
- 306-315
- ISSN
- 0022-3565 (ISSN-L)
- OpenAlex
- W2147542109
- Semantic Scholar
- 80efc9963d81a0ba4b0eb2793a4a416178bc42a1
- Cited by
- 106
- References
- 56
- Citations by year
- 2026: 1 · 2023: 1 · 2022: 1 · 2021: 3 · 2019: 1 · 2018: 1 · 2017: 2 · 2016: 7 · 2015: 10 · 2014: 10 · 2013: 10 · 2012: 11
- FWCI
- 5.17
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Pharmacology and Experimental Therapeutics (publishedVersion)
- PubMed (publishedVersion)
- Funders
- University of Utah
- National Institute of Mental Health (MH53631, R01MH053631)
- National Institute on Drug Abuse (DA012976, R01DA015767, R01DA012242, DA015767, DA12242)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nicotinic Acetylcholine Receptors Study
- Health Sciences › Medicine › Physiology › Smoking Behavior and Cessation
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- chronic nicotine, nicotinic acetylcholine receptors, alpha6 subunit, beta3 subunit, receptor down-regulation, striatum, superior colliculus, dopamine release, alpha-conotoxin MII, epibatidine, receptor subunit expression, nicotine withdrawal
- MeSH terms
- Amino Acid Sequence, Animals, Autoradiography, Brain, Dopamine, Male, Molecular Sequence Data, Nicotine, Receptors, Nicotinic, Rats, Sprague-Dawley, Conotoxins, Immunoprecipitation, Rats
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