Long-term nicotine treatment differentially regulates striatal α6α4β2* and α6(nonα4)β2* nAChR expression and function
Open accessAbstract
Nicotine treatment has long been associated with alterations in alpha4beta2(*) nicotinic acetylcholine receptor (nAChR) expression that modify dopaminergic function. However, the influence of long-term nicotine treatment on the alpha6beta2(*) nAChR, a subtype specifically localized on dopaminergic neurons, is less clear. Here we used voltammetry, as well as receptor binding studies, to identify the effects of nicotine on striatal alpha6beta2(*) nAChR function and expression. Long-term nicotine treatment via drinking water enhanced nonburst and burst endogenous dopamine release from rat striatal slices. In control animals, alpha6beta2(*) nAChR blockade with alpha-conotoxin MII (alpha-CtxMII) decreased release with nonburst stimulation but not with burst firing. These data in control animals suggest that varying stimulus frequencies differentially regulate alpha6beta2(*) nAChR-evoked dopamine release. In contrast, in nicotine-treated rats, alpha6beta2(*) nAChR blockade elicited a similar pattern of dopamine release with nonburst and burst firing. To elucidate the alpha6beta2(*) nAChR subtypes altered with long-term nicotine treatment, we used the novel alpha-CtxMII analog E11A in combination with alpha4 nAChR knockout mice. (125)I-alpha-CtxMII competition studies in striatum of knockout mice showed that nicotine treatment decreased the alpha6alpha4beta2(*) subtype but increased the alpha6(nonalpha4)beta2(*) nAChR population. These data indicate that alpha6beta2(*) nAChR-evoked dopamine release in nicotine-treated rats is mediated by the alpha6(nonalpha4)beta2(*) nAChR subtype and suggest that the alpha6alpha4beta2(*) nAChR and/or alpha4beta2(*) nAChR contribute to the differential effect of higher frequency stimulation on dopamine release under control conditions. Thus, alpha6beta2(*) nAChR subtypes may represent important targets for smoking cessation therapies and neurological disorders involving these receptors such as Parkinson's disease.
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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 [88]
The Introduction and Discussion report that chronic nicotine decreased striatal α6α4β2* receptors and increased α6(nonα4)β2* receptors in rodents. The Introduction also reports no change in α4α5β2 receptors, but the passages found do not address the claimed α3/α6 combination. (LLM, conf=0.85)
Experimental — accuracy not yet measuredα6β2* nAChRs have a critical and possibly dominant effect on dopaminergic neurotransmission in the mesolimbic and nigrostriatal dopaminergic system.
“Indeed, ␣62* nAChRs have been shown to have a critical and possibly dominant effect on dopaminergic neurotransmission in the mesolimbic and nigrostriatal dopaminergic system”
From Varenicline Is a Potent Partial Agonist at α6β2* Nicotinic Acetylcholine Receptors in Rat and Monkey Striatum (2012) · cites this paper as Perez et al., 2008
α6β2* nAChR function is modified by nicotine exposure.
“Moreover, their function is modified by nicotine exposure”
From Varenicline Is a Potent Partial Agonist at α6β2* Nicotinic Acetylcholine Receptors in Rat and Monkey Striatum (2012) · cites this paper as Perez et al., 2008
Nicotinic regulation of dopamine release likely involves an interplay between receptor activation and desensitization, and desensitization produces an effective channel block similar to that seen with nAChR antagonists.
“In addition, studies using cyclic voltametry indicate that this regulation of dopamine release most likely represents a complex interplay between nicotinic receptor activation and desensitization (Exley et al., 2008;Meyer et al., 2008;Perez et al., 2008)”
From Nicotinic receptor-mediated reduction in l-DOPA-induced dyskinesias may occur via desensitization (2010) · cites this paper as Perez et al., 2008
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- Authors
- Perez, X. A., Bordia, T., McIntosh, J. M., Grady, S. R., & Quik, M.
- Affiliations
- University of Colorado Boulder (US)
- Venue
- Molecular Pharmacology
- Publisher
- Elsevier BV
- Published
- 2008-09
- Volume
- 74
- Issue
- 3
- Pages
- 844-853
- ISSN
- 0026-895X (ISSN-L)
- PMC
- PMC2847502
- OpenAlex
- W2118793283
- Cited by
- 77
- References
- 44
- Citations by year
- 2025: 1 · 2024: 1 · 2023: 1 · 2021: 5 · 2020: 1 · 2019: 3 · 2018: 2 · 2017: 1 · 2016: 3 · 2015: 8 · 2014: 8 · 2013: 8 · 2012: 6
- FWCI
- 3.97
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular Pharmacology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Mental Health (MH53631, R01MH053631, R29MH053631)
- National Institute on Drug Abuse (DA 03194, R01DA003194, R01DA012242, DA12242)
- National Institute of General Medical Sciences (P01GM048677, GM48677)
- National Institute of Neurological Disorders and Stroke (R01NS047162, NS42091, NS47162, R01NS059910, 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, striatum, dopamine release, burst firing, alpha-conotoxin MII, dopaminergic neurons, smoking cessation, Parkinson's disease
- MeSH terms
- Action Potentials, Animals, Dopamine, Electrophysiology, Gene Expression Regulation, Male, Nicotine, Receptors, Nicotinic, Time Factors, Water, Down-Regulation, Neostriatum, Rats, Sprague-Dawley, Mice, Rats
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