Zhao-Shea, RubingDeGroot, Steven R.Liu, LiwangVallaster, MarkusPang, XueyanSu, QinGao, GuangpingRando, Oliver J.Martin, Gilles EGeorge, OlivierGardner, Paul D.Tapper, Andrew R.2022-08-232022-08-232015-04-212016-02-03<p>Nat Commun. 2015 Apr 21;6:6770. doi: 10.1038/ncomms7770. <a href="http://dx.doi.org/10.1038/ncomms7770">Link to article on publisher's site</a></p>2041-1723 (Linking)10.1038/ncomms777025898242https://hdl.handle.net/20.500.14038/33454<p>This article has been corrected. See <a href="http://www.ncbi.nlm.nih.gov/pubmed/26133887">Nat Commun. 2015 July 02; 6: 7625</a>.</p>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.en-USBehavioral NeurobiologySubstance Abuse and AddictionJournal Articlehttps://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=3005&amp;context=gsbs_sp&amp;unstamped=1https://escholarship.umassmed.edu/gsbs_sp/19848090573gsbs_sp/1984