title: Increased CRF signalling in a ventral tegmental area-interpeduncular nucleus-medial habenula circuit induces anxiety during nicotine withdrawal.
abstract: Increased anxiety is a prominent withdrawal symptom in abstinent smokers, yet the neuroanatomical and molecular bases underlying it are unclear. Here we show that withdrawal-induced anxiety increases activity of neurons in the interpeduncular intermediate (IPI), a subregion of the interpeduncular nucleus (IPN). IPI activation during nicotine withdrawal was mediated by increased corticotropin releasing factor (CRF) receptor-1 expression and signalling, which modulated glutamatergic input from the medial habenula (MHb). Pharmacological blockade of IPN CRF1 receptors or optogenetic silencing of MHb input reduced IPI activation and alleviated withdrawal-induced anxiety; whereas IPN CRF infusion in mice increased anxiety. We identified a mesointerpeduncular circuit, consisting of ventral tegmental area (VTA) dopaminergic neurons projecting to the IPN, as a potential source of CRF. Knockdown of CRF synthesis in the VTA prevented IPI activation and anxiety during nicotine withdrawal. These data indicate that increased CRF receptor signalling within a VTA-IPN-MHb circuit triggers anxiety during nicotine withdrawal.
authors.affiliation: Brudnick Neuropsychiatric Research Institute, Department of Psychiatry, University of Massachusetts Medical School, Worcester, Massachusetts 01604, USA.
authors.forename: Rubing
authors.initials: R
authors.lastname: Zhao-Shea
authors.affiliation: Brudnick Neuropsychiatric Research Institute, Department of Psychiatry, University of Massachusetts Medical School, Worcester, Massachusetts 01604, USA.
authors.forename: Steven R
authors.initials: SR
authors.lastname: DeGroot
authors.affiliation: Brudnick Neuropsychiatric Research Institute, Department of Psychiatry, University of Massachusetts Medical School, Worcester, Massachusetts 01604, USA.
authors.forename: Liwang
authors.initials: L
authors.lastname: Liu
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts 01604, USA.
authors.forename: Markus
authors.initials: M
authors.lastname: Vallaster
authors.affiliation: Brudnick Neuropsychiatric Research Institute, Department of Psychiatry, University of Massachusetts Medical School, Worcester, Massachusetts 01604, USA.
authors.forename: Xueyan
authors.initials: X
authors.lastname: Pang
authors.affiliation: Gene Therapy Center and Department of Microbiology and Physiology Systems, University of Massachusetts Medical School, Worcester, Massachusetts 01604, USA.
authors.forename: Qin
authors.initials: Q
authors.lastname: Su
authors.affiliation: Gene Therapy Center and Department of Microbiology and Physiology Systems, University of Massachusetts Medical School, Worcester, Massachusetts 01604, USA.
authors.forename: Guangping
authors.initials: G
authors.lastname: Gao
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts 01604, USA.
authors.forename: Oliver J
authors.initials: OJ
authors.lastname: Rando
authors.affiliation: Brudnick Neuropsychiatric Research Institute, Department of Psychiatry, University of Massachusetts Medical School, Worcester, Massachusetts 01604, USA.
authors.forename: Gilles E
authors.initials: GE
authors.lastname: Martin
authors.affiliation: Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, California 92037, USA.
authors.forename: Olivier
authors.initials: O
authors.lastname: George
authors.affiliation: Brudnick Neuropsychiatric Research Institute, Department of Psychiatry, University of Massachusetts Medical School, Worcester, Massachusetts 01604, 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, Massachusetts 01604, USA.
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Tapper
mesh_terms: D000818:Animals; D001007:Anxiety / Q000209:etiology*; D003346:Corticotropin-Releasing Hormone / Q000378:metabolism*; D019262:Habenula / Q000033:anatomy & histology / Q000502:physiology*; D066268:Interpeduncular Nucleus / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009415:Nerve Net; D009538:Nicotine / Q000009:adverse effects*; D018019:Receptors, Corticotropin-Releasing Hormone / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D013375:Substance Withdrawal Syndrome / Q000503:physiopathology; D017557:Ventral Tegmental Area / Q000502:physiology*; D000099052:CRF Receptor, Type 1
chemical_list: D018019:Receptors, Corticotropin-Releasing Hormone; D000099052:CRF Receptor, Type 1; D009538:Nicotine; D003346:Corticotropin-Releasing Hormone