Role of anterior insula cortex in context-induced relapse of nicotine-seeking

Hussein Ghareh, Isis Alonso-Lozares, Dustin Schetters, Rae J. Herman, Tim S. Heistek, Yvar Van Mourik, Philip Jean-Richard-dit-bressel, Gerald Zernig, Huibert D. Mansvelder, Taco J. De Vries, Nathan J. Marchant*

*Corresponding author for this work

Research output: Contribution to JournalArticleAcademicpeer-review

Abstract

Tobacco use is the leading cause of preventable death worldwide, and relapse during abstinence remains the critical barrier to successful treatment of tobacco addiction. During abstinence, environmental contexts associated with nicotine use can induce craving and contribute to relapse. The insular cortex (IC) is thought to be a critical substrate of nicotine addiction and relapse. However, its specific role in context-induced relapse of nicotine-seeking is not fully known. In this study, we report a novel rodent model of context-induced relapse to nicotine-seeking after punishment-imposed abstinence, which models self-imposed abstinence through increasing negative consequences of excessive drug use. Using the neuronal activity marker Fos we find that the anterior (aIC), but not the middle or posterior IC, shows increased activity during context-induced relapse. Combining Fos with retrograde labeling of aIC inputs, we show projections to aIC from contralateral aIC and basolateral amygdala exhibit increased activity during context-induced relapse. Next, we used fiber photometry in aIC and observed phasic increases in aIC activity around nicotine-seeking responses during self-administration, punishment, and the context-induced relapse tests. Next, we used chemogenetic inhibition in both male and female rats to determine whether activity in aIC is necessary for context-induced relapse. We found that chemogenetic inhibition of aIC decreased context-induced nicotine-seeking after either punishment-or extinction-imposed abstinence. These findings highlight the critical role nicotine-associated contexts play in promoting relapse, and they show that aIC activity is critical for this context-induced relapse following both punishment and extinction-imposed abstinence.

Original languageEnglish
Article numbere75609
Pages (from-to)1-27
Number of pages27
JournaleLife
Volume11
DOIs
Publication statusPublished - 10 May 2022

Bibliographical note

Funding Information:
The authors gratefully acknowledge the VUmc Histology Imaging Unit for their support & assistance in whole-slide imaging. The authors would like to thank Francesco Ferraguti for insightful comments in the preparation of this manuscript. The work was supported by an NWO VIDI grant (016.Vidi.188.022), Fulbright Fellowship to RH, and Austrian Science Fund (FWF) grant Signal Processing in Neurons (SPIN) W1206-12 to HG and GZ (graduate program Signal Processing In Neurons, https://www.​ neurospin.at/). The authors declare no conflict of interest.Funder Grant reference number AuthorNederlandse Organisatie voor Wetenschappelijk Onderzoek 016.Vidi.188.022 Nathan J MarchantFulbright Association Rae J HermanAustrian Science Fund Signal Processing in Neurons (SPIN) grant W1206-12 Hussein Ghareh Gerald Zernig.

Funding Information:
The authors gratefully acknowledge the VUmc Histology Imaging Unit for their support & assistance in whole-slide imaging. The authors would like to thank Francesco Ferraguti for insightful comments in the preparation of this manuscript. The work was supported by an NWO VIDI grant (016.Vidi.188.022), Fulbright Fellowship to RH, and Austrian Science Fund (FWF) grant Signal Processing in Neurons (SPIN) W1206-12 to HG and GZ (graduate program Signal Processing In Neurons, https://www. neurospin.at/). The authors declare no conflict of interest.

Publisher Copyright:
‍© Ghareh, Alonso-Lozares et al.

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