Differential Regulation of Mesolimbic α3 /α6β2 and α4β2 Nicotinic Acetylcholine Receptor Sites and Function after Long-Term Oral Nicotine to Monkeys
Abstract
Because the mesolimbic dopamine system plays a critical role in nicotine addiction/reinforcement and because nicotinic receptors regulate dopamine release, we initiated a study to evaluate the long-term effects of nicotine (>6 months at the final dose) on nicotinic acetylcholine receptor (nAChR) sites and function in the nucleus accumbens of nonhuman primates. Nicotine was given in the drinking water as this mode of administration is long-term but intermittent, thus resembling smoking in this aspect. We determined the effects of nicotine treatment on function and binding of the alpha3/alpha6beta2* and alpha4beta2* nAChRs subtypes in nucleus accumbens, a region directly implicated in the addictive effects of nicotine. To evaluate function, we measured nicotine and K+-evoked [3H]dopamine release from nucleus accumbens synaptosomes. Changes in alpha4beta2* and alpha3/alpha6beta2* nAChRs were measured using 125I-epibatidine, [125I]A85380 [5-[125I]iodo-3(2(S)-azetidinylmethoxy) pyridine] and 125I-alpha-conotoxin MII autoradiography. Chronic nicotine treatment, which led to plasma nicotine levels in the range of smokers, significantly increased nucleus accumbens alpha4beta2* nAChR sites and function compared with control. By contrast, this treatment did not significantly change alpha3/alpha6beta2* nAChR sites or evoked dopamine release in this region compared with control. Thus, these data are distinct from previous results in striatum in which the same nicotine treatment paradigm…
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Different β2*-subunit combinations appear to be differentially regulated by nicotine, with α3/α6 and α6α4β2* and α5α4β2* not upregulating or decreasing in response to nicotine while α6β2 (nonα4) nAChR increase in response to nicotine.
“Importantly, different β2*-subunit combinations appear to be differentially regulated by nicotine, with α3/α6 and α6α4β2* and α5α4β2* not upregulating or decreasing in response to nicotine38, 85-88 while α6β2 (nonα4) nAChR increase in response to nicotine88.”
From β2-Nicotinic Acetylcholine Receptor Availability During Acute and Prolonged Abstinence From Tobacco Smoking (2009) · cites this paper as [86]
Cites
Nicotine reinforcement and cognition restored by targeted expression of nicotinic receptors
Maskos, U., Molles, B. E., Pons, S., Besson, M., Guiard, B. P., Guilloux, J.-P., Evrard, A., Cazala, P., Cormier, A., Mameli-Engvall, M., et al. (2005) · Nature · doi:10.1038/nature03694 · Cited by 566 · cited 3× · see citing works
“This interpretation is consistent with previous work in nAChR mutant mice, suggesting that 4 2* nAChRs are important in nicotine addiction (Picciotto et al., 1998; Klink et al., 2001; Tapper et al., 2004; Maskos et al., 2005; Walters et al., 2006).”
ResultNicotinic Cholinergic Receptor Binding Sites in the Brain: Regulation in Vivo
Schwartz, R. D., & Kellar, K. J. (1983) · Science · doi:10.1126/science.6828889 · Cited by 479 · see citing works
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Self-citationNicotine: from molecular mechanisms to behaviour
Wonnacott, S., Sidhpura, N., & Balfour, D. J. (2005) · Current Opinion in Pharmacology · doi:10.1016/j.coph.2004.12.002 · Cited by 263 · see citing works
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“The 4 2* nAChR population is increased in rodent brain, with chronic nicotine treatment, and is also elevated in the brains of smokers (Marks et al., 1983; Schwartz and Kellar, 1983; Benwell et al., 1988).”
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PICCIOTTO, M., ADDY, N., MINEUR, Y., & BRUNZELL, D. (2008) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2007.12.005 · Cited by 451 · see citing works
Reward, addiction, withdrawal to nicotine
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“…differs among the diverse subtypes, varies among brain regions for the same nAChR subtype, and depends on the contingency of nicotine administration (Gaimarri et al. 2007, Marks et al. 1983, McCallum et al. 2006, Metaxas et al. 2010, Nguyen et al. 2004, Pauly et al. 1996, Schwartz & Kellar 1983).”
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- Authors
- McCallum, S. E., Parameswaran, N., Bordia, T., Fan, H., McIntosh, J. M., & Quik, M.
- Affiliations
- Johns Hopkins University (US)
- Venue
- The Journal of Pharmacology and Experimental Therapeutics
- Publisher
- Elsevier BV
- Published
- 2006-07
- Volume
- 318
- Issue
- 1
- Pages
- 381-388
- ISSN
- 0022-3565 (ISSN-L)
- OpenAlex
- W2252376906
- Cited by
- 48
- References
- 9
- Citations by year
- 2021: 1 · 2019: 2 · 2018: 4 · 2016: 4 · 2015: 2 · 2014: 5 · 2013: 4 · 2012: 3
- FWCI
- 2.31
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Pharmacology and Experimental Therapeutics (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Mental Health (MH53631, R01MH053631)
- National Institute of Neurological Disorders and Stroke (R01NS047162, NS42091, NS47162, R01NS042091)
- 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
- nicotinic acetylcholine receptors, alpha4beta2 nAChR, nicotine, nicotine dependence, mesolimbic dopamine system, nucleus accumbens, dopamine release, receptor binding, non-human primates, epibatidine, alpha-conotoxin MII
- MeSH terms
- Administration, Oral, Animals, Binding Sites, Brain, Dose-Response Relationship, Drug, Female, Limbic System, Nicotine, Receptors, Nicotinic, Saimiri, Time Factors
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