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4 2 Nicotinic Acetylcholine Receptors on Dopaminergic Neurons Mediate Nicotine Reward and Anxiety Relief
Open accessAbstract
Nicotine is the primary psychoactive substance in tobacco, and it exerts its effects by interaction with various subtypes of nicotinic acetylcholine receptors (nAChRs) in the brain. One of the major subtypes expressed in brain, the α4β2-nAChR, endogenously modulates neuronal excitability and thereby, modifies certain normal as well as nicotine-induced behaviors. Although α4-containing nAChRs are widely expressed across the brain, a major focus has been on their roles within midbrain dopaminergic regions involved in drug addiction, mental illness, and movement control in humans. We developed a unique model system to examine the role of α4-nAChRs within dopaminergic neurons by a targeted genetic deletion of the α4 subunit from dopaminergic neurons in mice. The loss α4 mRNA and α4β2-nAChRs from dopaminergic neurons was confirmed, as well as selective loss of α4β2-nAChR function from dopaminergic but not GABAergic neurons. Two behaviors central to nicotine dependence, reward and anxiety relief, were examined. α4-nAChRs specifically on dopaminergic neurons were demonstrated to be necessary for nicotine reward as measured by nicotine place preference, but not for another drug of addiction, cocaine. α4-nAChRs are necessary for the anxiolytic effects of nicotine in the elevated plus maze, and elimination of α4β2-nAChRs specifically from dopaminergic neurons decreased sensitivity to the anxiolytic effects of nicotine. Deletion of α4-nAChRs specifically from dopaminergic neurons also increased sensitivity to nicotine-induced locomotor depression; however, nicotine-induced hypothermia was unaffected. This is the first work to develop a dopaminergic specific deletion of a nAChR subunit and examine resulting changes in nicotine-related behaviors.
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“Similarly, knockout of the α4 subunit abolishes intracerebroventricular (i.c.v.) selfadministration of nicotine, consistent with evidence that α4/β2 Ã nAChRs are required for depolarization of DA neurons in the VTA (Exley et al. 2011;McGranahan et al. 2011).”
From Mechanisms of Nicotine Addiction (2021) · cites this paper as McGranahan et al. 2011
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“In contrast, in mice with constitutive knockout of the α6 subunit, intra-VTA selfadministration of nicotine is not disrupted, whereas α4 Ã nAChRs are necessaryand sufficient for both intra-VTA self-administration, as well as nicotine-induced increases in firing of DA neurons (Exley et al. 2011;McGranahan et al. 2011).”
From Mechanisms of Nicotine Addiction (2021) · cites this paper as McGranahan et al. 2011
Experimental — accuracy not yet measuredIn the citing paper
“particularly because the addictive effects of nicotine are mediated primarily through stimulation of nAChRs in the VTA (Drenan et al., 2008; Maskos et al., 2005; McGranahan et al., 2011; Picciotto et al., 1998).”
From Acetylcholine as a Neuromodulator: Cholinergic Signaling Shapes Nervous System Function and Behavior (2012) · cites this paper as McGranahan et al., 2011
In the citing paper
“mice lacking β2* nAChRs in dopamine neurons of the VTA lack anxiolytic responses to nicotine and are insensitive to nicotine reward (McGranahan et al., 2011)”
From Mood and anxiety regulation by nicotinic acetylcholine receptors: A potential pathway to modulate aggression and related behavioral states (2015) · cites this paper as McGranahan et al., 2011
In the citing paper
“Nicotine reinforcement and reward is mediated through nAChRs in the mesolimbic system (Maskos et al., 2005; McGranahan et al., 2011; Tolu et al., 2012)”
From Mood and anxiety regulation by nicotinic acetylcholine receptors: A potential pathway to modulate aggression and related behavioral states (2015) · cites this paper as McGranahan et al., 2011
In the citing paper
“McGranahan, Patzlaff, Grady, Heinemann, and Booker (2011) found that selective elimination of α4β2 nAChRs located on dopaminergic neurons reversed the anxiolytic effects of nicotine.”
From Nicotine addiction and psychiatric disorders (2015) · cites this paper as McGranahan et al. (2011)
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Metadata
- Authors
- McGranahan, T. M., Patzlaff, N. E., Grady, S. R., Heinemann, S. F., & Booker, T. K.
- Affiliations
- Salk Institute for Biological Studies (US)
- University of Colorado Boulder (US)
- ORCID
- McGranahan, T. M.
- Venue
- Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2011-07-27
- Volume
- 31
- Issue
- 30
- Pages
- 10891-10902
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC3539812
- OpenAlex
- W1973295491
- Cited by
- 165
- References
- 60
- Citations by year
- 2026: 9 · 2025: 10 · 2024: 20 · 2023: 12 · 2022: 4 · 2021: 9 · 2020: 12 · 2019: 5 · 2018: 3 · 2017: 9 · 2016: 10 · 2015: 17 · 2014: 14 · 2013: 21 · 2012: 9
- FWCI
- 5.85
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Neuroscience (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute on Alcohol Abuse and Alcoholism (AA13018, R01AA013018)
- National Institute on Drug Abuse (DA018247, R01DA018247, DA012242, R01DA003194, DA003194, R01DA012242)
- National Institute of Neurological Disorders and Stroke (NS10830, F32NS010830)
- 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, alpha4beta2 nAChR, dopaminergic neurons, nicotine reward, nicotine dependence, midbrain dopaminergic system, cocaine reward
- MeSH terms
- Analysis of Variance, Animals, Anxiety, Behavior, Animal, Body Temperature, Conditioning, Operant, Disease Models, Animal, Dopamine, Female, gamma-Aminobutyric Acid, Glutamate Decarboxylase, Male, Mesencephalon, Mice, Inbred C57BL, Neurons, Nicotine, Protein Binding, Pyridines, Receptors, Nicotinic, Reward, Synaptosomes, Tritium, Mice, Knockout, Nicotinic Agonists, Bridged Bicyclo Compounds, Heterocyclic, Dopamine Plasma Membrane Transport Proteins, Mice
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