Habenular α5 nicotinic receptor subunit signalling controls nicotine intake
Open accessAbstract
Genetic variation in CHRNA5, the gene encoding the α5 nicotinic acetylcholine receptor subunit, increases vulnerability to tobacco addiction and lung cancer, but the underlying mechanisms are unknown. Here we report markedly increased nicotine intake in mice with a null mutation in Chrna5. This effect was 'rescued' in knockout mice by re-expressing α5 subunits in the medial habenula (MHb), and recapitulated in rats through α5 subunit knockdown in MHb. Remarkably, α5 subunit knockdown in MHb did not alter the rewarding effects of nicotine but abolished the inhibitory effects of higher nicotine doses on brain reward systems. The MHb extends projections almost exclusively to the interpeduncular nucleus (IPN). We found diminished IPN activation in response to nicotine in α5 knockout mice. Further, disruption of IPN signalling increased nicotine intake in rats. Our findings indicate that nicotine activates the habenulo-interpeduncular pathway through α5-containing nAChRs, triggering an inhibitory motivational signal that acts to limit nicotine intake.
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α5 knockout mice consumed more nicotine only when higher unit doses were available.
“Interestingly, the knockout mice consumed more nicotine only when higher unit doses of the drug were available (Fowler et al. 2011).”
From Mechanisms of Nicotine Addiction (2021) · cites this paper as Fowler et al. 2011
In “α5* nAChRs control nicotine intake” (page unavailable), the paper reports that knockout mice consumed greater amounts as the unit dose increased and responded more vigorously especially at higher doses. It does not establish the claim’s stricter “only” condition: the passage says “especially,” not that increased consumption occurred exclusively at higher doses. (LLM, conf=0.86)
Experimental — accuracy not yet measuredChemical inactivation of the MHb or IPN with lidocaine, or disruption of NMDA receptor-mediated glutamatergic transmission with LY2358959, increased nicotine self-administration in rats similarly to α5 knockout.
“Chemical inactivation of the MHb or the IPN using the local anesthetic lidocaine, or disruption of N-methyl-D-aspartate (NMDA) receptor-mediated glutamatergic transmission in these sites using the competitive antagonist LY2358959, increased nicotine self-administration behavior in rats in a manner similar to the α5 nAChR subunit knockout mice (Fowler et al. 2011).”
From Mechanisms of Nicotine Addiction (2021) · cites this paper as Fowler et al. 2011
In “Habenular-IPN activity limits nicotine intake,” lidocaine inactivation of the IPN or MHb and NMDA-receptor antagonism at those sites increased nicotine self-administration in rats, consistent with the knockout findings reported elsewhere in the paper. The source names the antagonist LY235959, not LY2358959; it also reports the MHb effects only at a higher nicotine dose. Page numbers were not provided in the supplied passages. (LLM, conf=0.88)
Experimental — accuracy not yet measuredα5 nicotinic acetylcholine receptors in the habenula appear to modulate aversive responses to large doses of nicotine, and habenular α2 receptors along with α5 are involved in nicotine withdrawal.
“This hypothesis is also consistent with the finding that α5 nicotinic acetylcholine receptors in the habenula appear to modulate aversive responses to large doses of nicotine48 and, along with habenular α2 receptors, nicotine withdrawal (tables 1, 2, circuit 9).”
From Neurobiology of addiction: a neurocircuitry analysis (2016) · cites this paper as [48]
Mice with a null mutation in the α5 subunit intravenously self-administered far more nicotine than wild-type littermates.
“Consistent with an important role for α5 Ã nAChRs in regulating nicotine intake, it was recently shown that mice with null mutation in this subunit intravenously self-administered far more nicotine than their wild-type littermates (Fowler et al. 2011).”
From Mechanisms of Nicotine Addiction (2021) · cites this paper as Fowler et al. 2011
The MHb-IPN pathway of α5 knockout mice was far less sensitive to nicotine-induced activation than that of wild-type mice, as measured by Fos immunoreactivity.
“By using Fos immunoreactivity as a measure of neuronal activation, it was shown that the MHb-IPN pathway of the knockout mice was far less sensitive to nicotine-induced activation than wild-type mice (Fowler et al. 2011).”
From Mechanisms of Nicotine Addiction (2021) · cites this paper as Fowler et al. 2011
Virus-mediated reexpression of the α5 nAChR subunit in the MHb-IPN pathway of knockout mice abolished the increased nicotine intake seen at higher doses.
“Virus-mediated reexpression of the α5 nAChR subunit in the MHb-IPN pathway of knockout mice abolished the increased nicotine intake seen at higher doses of nicotine (Fowler et al. 2011).”
From Mechanisms of Nicotine Addiction (2021) · cites this paper as Fowler et al. 2011
Knockdown of α5 nAChR subunits in the MHb-IPN pathway in rats decreased sensitivity to the aversive actions of higher nicotine doses compared with controls, as measured by ICSS reward thresholds.
“Finally, knockdown of α5 nAChR subunits in the MHb-IPN pathway in rats decreased their sensitivity to the reward-inhibiting (i.e., aversive) actions of higher nicotine doses compared with control rats, as measured by nicotine-induced elevations of intracranial self-stimulation (ICSS) reward thresholds (Fowler et al. 2011).”
From Mechanisms of Nicotine Addiction (2021) · cites this paper as Fowler et al. 2011
RNA interference-mediated knockdown of α5 nAChR subunits in the MHb-IPN pathway in rats increased nicotine intake at higher unit doses, similar to α5 knockout mice.
“Conversely, RNA interference-mediated knockdown of α5 nAChR subunits in the MHb-IPN pathway in rats resulted in increased nicotine intake at higher unit doses of the drug, very similar to the same behavioral profile detected in the knockout mice (Fowler et al. 2011).”
From Mechanisms of Nicotine Addiction (2021) · cites this paper as Fowler et al. 2011
The cholinoceptive cell population in the medial habenula is associated with the aversive effects of nicotine.
“Additionally, the cholinoceptive cellular population within the medial habenula (MHb) has been associated with the aversive effects of nicotine (Fowler et al. 2011).”
From Nicotine Withdrawal (2015) · cites this paper as Fowler et al. 2011
Re-expression of α5 in the MHb or IPN restores nicotine self-administration to wild type levels.
“However, lentiviral-based re-expression of the α5 subunit in the MHb or the IPN is sufficient to bring nicotine self-administration back to wild type levels [80].”
From Mechanistic insights into nicotine withdrawal (2011) · cites this paper as [80]
α5-containing nAChRs in the MHb control the amount of nicotine self-administered, as α5−/− mice self-administer doses that normally cause aversion in wild type.
“A recent report suggests that α5-containing nAChRs in the MHb are key to the control of the amounts of nicotine self-administered as α5−/− mice continue to self-administer nicotine at doses that normally elicit strong aversion in wild type animals [79, 80].”
From Mechanistic insights into nicotine withdrawal (2011) · cites this paper as [80]
The MHb/IPN axis is emerging as a brain circuit involved in processing anti-reward stimuli and nicotine withdrawal.
“which, as discussed in section 2.3, is emerging as a brain circuit involved in the processing of anti-reward stimuli and nicotine withdrawal [11, 80, 222].”
From Mechanistic insights into nicotine withdrawal (2011) · cites this paper as [80]
Varenicline's interactions with α3β4-, α2-, or α6-containing nAChRs might contribute to its therapeutic effects.
“Varenicline’s interactions with α3β4-, α2-, or α6-containing nAChRs might also contribute to its therapeutic effects given the role of those receptors in both the rewarding and/or aversive effects of nicotine [11, 13, 80, 81].”
From Mechanistic insights into nicotine withdrawal (2011) · cites this paper as [80]
In nicotine, a5 nicotinic receptors in the habenula appear to modulate aversive responses to large doses of nicotine.
“In the case of nicotine, a5 nicotinic receptors in the habenula appear to modulate the aversive responses to large doses of nicotine (155), and a5 and a2 receptors to modulate nicotine withdrawal (156).”
From Obesity and addiction: Neurobiological overlaps (2013) · cites this paper as [155]
In the case of nicotine, the α5 nicotinic receptors in the habenula appear to modulate the aversive responses to large doses of nicotine, and the α5 and α2 receptors in the habenula are implicated in nicotine withdrawal.
“In the case of nicotine, the α5 nicotinic receptors in the habenula appear to modulate the aversive responses to large doses of nicotine (Fowler et al 2011) and the α5 and α2 receptors in the habenula are implicated in nicotine withdrawal (Salas et al 2009).”
From Food and Drug Reward: Overlapping Circuits in Human Obesity and Addiction (2011) · cites this paper as Fowler et al 2011
Decreasing the expression of nicotinic acetylcholine receptors containing the α5 subunit in the MHb results in increased nicotine self-administration, suggesting that this cholinergic system normally acts as a brake on drug reward.
“Decreasing the expression of nAChRs containing the α5 subunit in the MHb results in increased nicotine self-administration (Fowler et al., 2011), suggesting that this cholinergic system normally acts as a brake on drug reward.”
From Acetylcholine as a Neuromodulator: Cholinergic Signaling Shapes Nervous System Function and Behavior (2012) · cites this paper as Fowler et al., 2011
The most likely reasons for the null MDD GWAS results are particularly high heterogeneity of MDD and insufficient power arising from its lower heritability.
“The most likely reasons for these results are particularly high heterogeneity of MDD and insufficient power arising from its lower heritability. 108”
From Genetic architectures of psychiatric disorders: the emerging picture and its implications (2012) · cites this paper as [108]
The PGC GWAS mega-analysis of 9,240 MDD cases and 9,519 controls (replication in 6,783 MDD cases) revealed no findings of genome-wide significance.
“The PGC GWAS mega-analysis of 9,240 MDD cases and 9,519 controls (replication in 6,783 MDD cases) revealed no findings of genome-wide significance. 108”
From Genetic architectures of psychiatric disorders: the emerging picture and its implications (2012) · cites this paper as [108]
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“This result suggests that α5-containing nAChRs in the MHb are key to controlling the amounts of nicotine self-administered (Fowler et al. 2011).”
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- Authors
- Fowler, C. D., Lu, Q., Johnson, P. M., Marks, M. J., & Kenny, P. J.
- Affiliations
- Scripps Research Institute (US)
- University of Colorado Boulder (US)
- Corresponding author
- Kenny, Paul J.
- Venue
- Nature
- Published
- 2011-01-30
- Volume
- 471
- Issue
- 7340
- Pages
- 597-601
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3079537
- OpenAlex
- W1996499810
- Cited by
- 663
- References
- 62
- Citations by year
- 2026: 22 · 2025: 30 · 2024: 24 · 2023: 34 · 2022: 21 · 2021: 31 · 2020: 78 · 2019: 44 · 2018: 44 · 2017: 34 · 2016: 45 · 2015: 50 · 2014: 60 · 2013: 57 · 2012: 49
- FWCI
- 26.98
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Institute on Drug Abuse (P30DA015663, F32DA026693, DA020686, R01DA020686, DA026693, R37DA020686)
- 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 › Neurotransmitter Receptor Influence on Behavior
- Keywords
- CHRNA5, nicotine use, tobacco dependence, medial habenula, interpeduncular nucleus, nicotine reward, smoking cessation, lung cancer susceptibility
- MeSH terms
- Animals, Female, Male, Nicotine, Receptors, Nicotinic, Reward, Tobacco Use Disorder, Signal Transduction, Mice, Knockout, Habenula, Mice, Rats
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