title: Habenula cholinergic neurons regulate anxiety during nicotine withdrawal via nicotinic acetylcholine receptors.
abstract: Cholinergic neurons in the medial habenula (MHb) modulate anxiety during nicotine withdrawal although the molecular neuroadaptation(s) within the MHb that induce affective behaviors during nicotine cessation is largely unknown. MHb cholinergic neurons are unique in that they robustly express neuronal nicotinic acetylcholine receptors (nAChRs), although their behavioral role as autoreceptors in these neurons has not been described. To test the hypothesis that nAChR signaling in MHb cholinergic neurons could modulate anxiety, we expressed novel "gain of function" nAChR subunits selectively in MHb cholinergic neurons of adult mice. Mice expressing these mutant nAChRs exhibited increased anxiety-like behavior that was alleviated by blockade with a nAChR antagonist. To test the hypothesis that anxiety induced by nicotine withdrawal may be mediated by increased MHb nicotinic receptor signaling, we infused nAChR subtype selective antagonists into the MHb of nicotine naïve and withdrawn mice. While antagonists had little effect on nicotine naïve mice, blocking α4β2 or α6β2, but not α3β4 nAChRs in the MHb alleviated anxiety in mice undergoing nicotine withdrawal. Consistent with behavioral results, there was increased functional expression of nAChRs containing the α6 subunit in MHb neurons that also expressed the α4 subunit. Together, these data indicate that MHb cholinergic neurons regulate nicotine withdrawal-induced anxiety via increased signaling through nicotinic receptors containing the α6 subunit and point toward nAChRs in MHb cholinergic neurons as molecular targets for smoking cessation therapeutics.
authors.affiliation: Brudnick Neuropsychiatric Research Institute, Department of Psychiatry, University of Massachusetts Medical School, Worcester, MA 01604, USA; Program in Neuroscience, University of Massachusetts Medical School, Worcester, MA 01655, USA.
authors.forename: Xueyan
authors.initials: X
authors.lastname: Pang
authors.affiliation: Brudnick Neuropsychiatric Research Institute, Department of Psychiatry, University of Massachusetts Medical School, Worcester, MA 01604, USA.
authors.forename: Liwang
authors.initials: L
authors.lastname: Liu
authors.affiliation: Brudnick Neuropsychiatric Research Institute, Department of Psychiatry, University of Massachusetts Medical School, Worcester, MA 01604, USA; Program in Neuroscience, University of Massachusetts Medical School, Worcester, MA 01655, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Ngolab
authors.affiliation: Brudnick Neuropsychiatric Research Institute, Department of Psychiatry, University of Massachusetts Medical School, Worcester, MA 01604, USA.
authors.forename: Rubing
authors.initials: R
authors.lastname: Zhao-Shea
authors.affiliation: George E. Wahlen Veterans Affairs Medical Center, Salt Lake City, UT 84108, USA; Department of Psychiatry, University of Utah, Salt Lake City, UT 84112, USA; Department of Biology, University of Utah, Salt Lake City, UT 84112, USA.
authors.forename: J Michael
authors.initials: JM
authors.lastname: McIntosh
authors.affiliation: Brudnick Neuropsychiatric Research Institute, Department of Psychiatry, University of Massachusetts Medical School, Worcester, MA 01604, USA; Program in Neuroscience, University of Massachusetts Medical School, Worcester, MA 01655, USA.
authors.forename: Paul D
authors.initials: PD
authors.lastname: Gardner
authors.affiliation: Brudnick Neuropsychiatric Research Institute, Department of Psychiatry, University of Massachusetts Medical School, Worcester, MA 01604, USA; Program in Neuroscience, University of Massachusetts Medical School, Worcester, MA 01655, USA. Electronic address: andrew.tapper@umassmed.edu.
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Tapper
mesh_terms: D000818:Animals; D001007:Anxiety / Q000378:metabolism* / Q000523:psychology; D059329:Cholinergic Neurons / Q000187:drug effects / Q000378:metabolism*; D019262:Habenula / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009538:Nicotine / Q000009:adverse effects*; D018722:Nicotinic Agonists / Q000494:pharmacology; D011978:Receptors, Nicotinic / Q000096:biosynthesis*; D013375:Substance Withdrawal Syndrome / Q000378:metabolism* / Q000523:psychology
chemical_list: D018722:Nicotinic Agonists; D011978:Receptors, Nicotinic; C403530:nicotinic receptor alpha3beta4; C403531:nicotinic receptor alpha4beta2; C104518:nicotinic receptor alpha6; D009538:Nicotine
keywords: Acetylcholine; Anxiety; Habenula; Nicotine; Withdrawal