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

Student Author(s)

Steven Degroot; Xueyan Pang; Markus Vallaster

Academic Program


UMMS Affiliation

Brudnick Neuropsychiatric Research Institute; Department of Psychiatry; Department of Biochemistry and Molecular Pharmacology; Gene Therapy Center; Department of Microbiology and Physiological Systems; Graduate School of Biomedical Sciences; Martin Lab; Gardner Lab; Tapper Lab

Publication Date


Document Type



Behavioral Neurobiology | Substance Abuse and Addiction


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.

DOI of Published Version



Nat Commun. 2015 Apr 21;6:6770. doi: 10.1038/ncomms7770. Link to article on publisher's site

Journal/Book/Conference Title

Nature communications


This article has been corrected. See Nat Commun. 2015 July 02; 6: 7625.

Related Resources

Link to Article in PubMed

PubMed ID