ArticleFrontiers in human neuroscience2014
Habenular expression of rare missense variants of the β4 nicotinic receptor subunit alters nicotine consumption.
Article in Frontiers in human neuroscience, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 39 citations in OpenAlex.
- Nicotinic Receptors in the Medial Habenula to Interpeduncular Nucleus Pathway: Modulators of Reward, Aversion and Emotion.The European journal of neuroscience · 2025Review
- Transcriptomic Analysis of the Human Habenula in Schizophrenia.The American journal of psychiatry · 2025Article
- The influence of stress and social defeat on neurobiological reinforcement mechanisms across reward to withdrawal in nicotine addiction.Psychopharmacology · 2025Review
- Rare Missense Variants of the Human β4 Subunit Alter Nicotinic α3β4 Receptor Plasma Membrane Localisation.Molecules (Basel, Switzerland) · 2023Article
- Neurobiological Mechanisms of Nicotine Reward and Aversion.Pharmacological reviews · 2022Review
- Addiction-related neuroadaptations following chronic nicotine exposure.Journal of neurochemistry · 2021Review
- β4-Nicotinic Receptors Are Critically Involved in Reward-Related Behaviors and Self-Regulation of Nicotine Reinforcement.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2020Article
- Mu opioid receptors in the medial habenula contribute to naloxone aversion.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2020Article
- The α5 Nicotinic Acetylcholine Receptor Subunit Differentially Modulates α4β2Frontiers in synaptic neuroscience · 2020Review
- From controlled to compulsive drug-taking: The role of the habenula in addiction.Neuroscience and biobehavioral reviews · 2019Review
- Nicotine aversion is mediated by GABAergic interpeduncular nucleus inputs to laterodorsal tegmentum.Nature communications · 2018Article
- Transcriptomic Characterization of the Human Habenula Highlights Drug Metabolism and the Neuroimmune System.Frontiers in neuroscience · 2018Article
- Neuronal and Extraneuronal Nicotinic Acetylcholine Receptors.Current neuropharmacology · 2018Review
- Retrograde inhibition by a specific subset of interpeduncular α5 nicotinic neurons regulates nicotine preference.Proceedings of the National Academy of Sciences of the United States of America · 2017Article
- Isoform-specific mechanisms of α3β4*-nicotinic acetylcholine receptor modulation by the prototoxin lynx1.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2017Article
- Therapeutic concentrations of varenicline in the presence of nicotine increase action potential firing in human adrenal chromaffin cells.Journal of neurochemistry · 2017Article
- Converging findings from linkage and association analyses on susceptibility genes for smoking and other addictions.Molecular psychiatry · 2016Review
- Habenula cholinergic neurons regulate anxiety during nicotine withdrawal via nicotinic acetylcholine receptors.Neuropharmacology · 2016Article
- Role of β4* Nicotinic Acetylcholine Receptors in the Habenulo-Interpeduncular Pathway in Nicotine Reinforcement in Mice.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2016Article
- Contribution of Variants in CHRNA5/A3/B4 Gene Cluster on Chromosome 15 to Tobacco Smoking: From Genetic Association to Mechanism.Molecular neurobiology · 2016Review
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Authors and funding
8 authors at 3 institutions in 3 countries.
Funding
Abstract
The CHRNA5-CHRNA3-CHRNB4 gene cluster, encoding the α5, α3, and β4 nicotinic acetylcholine receptor (nAChR) subunits, has been linked to nicotine dependence. The habenulo-interpeduncular (Hb-IPN) tract is particularly enriched in α3β4 nAChRs. We recently showed that modulation of these receptors in the medial habenula (MHb) in mice altered nicotine consumption. Given that β4 is rate-limiting for receptor activity and that single nucleotide polymorphisms (SNPs) in CHRNB4 have been linked to altered risk of nicotine dependence in humans, we were interested in determining the contribution of allelic variants of β4 to nicotine receptor activity in the MHb. We screened for missense SNPs that had allele frequencies >0.0005 and introduced the corresponding substitutions in Chrnb4. Fourteen variants were analyzed by co-expression with α3. We found that β4A90I and β4T374I variants, previously shown to associate with reduced risk of smoking, and an additional variant β4D447Y, significantly increased nicotine-evoked current amplitudes, while β4R348C, the mutation most frequently encountered in sporadic amyotrophic lateral sclerosis (sALS), showed reduced nicotine currents. We employed lentiviruses to express β4 or β4 variants in the MHb. Immunoprecipitation studies confirmed that β4 lentiviral-mediated expression leads to specific upregulation of α3β4 but not β2 nAChRs in the Mhb. Mice injected with the β4-containing virus showed pronounced aversion to nicotine as previously observed in transgenic Tabac mice overexpressing Chrnb4 at endogenous sites including the MHb. Habenular expression of the β4 gain-of-function allele T374I also resulted in strong aversion, while transduction with the β4 loss-of function allele R348C failed to induce nicotine aversion. Altogether, these data confirm the critical role of habenular β4 in nicotine consumption, and identify specific SNPs in CHRNB4 that modify nicotine-elicited currents and alter nicotine consumption in mice.
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