Increased CRF signalling in a ventral tegmental area-interpeduncular nucleus-medial habenula circuit induces anxiety during nicotine withdrawal

Rubing Zhao-Shea, Steven R. DeGroot, Liwang Liu, Markus Vallaster, Xueyan Pang, Qin Su, Guangping Gao, Oliver J. Rando, Gilles E. Martin, Olivier George, Paul D. Gardner and Andrew R. Tapper ()
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Rubing Zhao-Shea: Brudnick Neuropsychiatric Research Institute, University of Massachusetts Medical School
Steven R. DeGroot: Brudnick Neuropsychiatric Research Institute, University of Massachusetts Medical School
Liwang Liu: Brudnick Neuropsychiatric Research Institute, University of Massachusetts Medical School
Markus Vallaster: University of Massachusetts Medical School
Xueyan Pang: Brudnick Neuropsychiatric Research Institute, University of Massachusetts Medical School
Qin Su: University of Massachusetts Medical School
Guangping Gao: University of Massachusetts Medical School
Oliver J. Rando: University of Massachusetts Medical School
Gilles E. Martin: Brudnick Neuropsychiatric Research Institute, University of Massachusetts Medical School
Olivier George: Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute
Paul D. Gardner: Brudnick Neuropsychiatric Research Institute, University of Massachusetts Medical School
Andrew R. Tapper: Brudnick Neuropsychiatric Research Institute, University of Massachusetts Medical School

Nature Communications, 2015, vol. 6, issue 1, 1-14

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms7770

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