The interpeduncular nucleus blunts the rewarding effect of nicotine

Jehl, J.; Ciscato, M.; Vicq, E.; Dejean de la Batie, G.; Guyon, N.; Mondoloni, S.; Frangieh, J.; Nguyen, C.; Hardelin, J.-P.; Marti, F.; Corringer, P.-J.; Faure, P.; Mourot, A.

doi:10.1101/2023.10.05.561018

bioRxiv · 10.1101/2023.10.05.561018

The interpeduncular nucleus blunts the rewarding effect of nicotine

Jehl, J.·Ciscato, M.·Vicq, E.·Dejean de la Batie, G.·Guyon, N.·Mondoloni, S.·Frangieh, J.·Nguyen, C.·Hardelin, J.-P.·Marti, F.·Corringer, P.-J.·Faure, P.·Mourot, A.

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Abstract

Nicotine, by stimulating ventral tegmental area (VTA) dopaminergic neurons, has a rewarding effect that drives tobacco consumption. In turn, the interpeduncular nucleus (IPN) is thought to become activated at high nicotine doses to restrict drug intake. However, the dynamics of the IPN response to nicotine and its impact on the rewarding effect of the drug remain unknown. To address this issue, we have developed a genetically-modified mouse model, in which a "suicide" antagonist of nicotinic acetylcholine receptors (nAChRs) selectively attaches to a designer {beta}4 nAChR subunit. By locally infusing this antagonist in the IPN, we achieved pharmacologically-specific and sustained antagonism of nAChRs containing the {beta}4 subunit. By combining this chemogenetic method with in vivo electrophysiology, we show that even at low doses, nicotine activates and inhibits two different populations of IPN neurons, and that {beta}4-containing nAChRs are only involved in the activation response. Furthermore, blocking the response to nicotine selectively in the IPN increased both the sensitivity of the VTA to the drug and its rewarding effect in a conditioned place preference paradigm. These findings indicate that the IPN is engaged across a large range of nicotine doses and acts as a regulatory brake on the nicotine reward circuit.

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Jehl, J., Ciscato, M., Vicq, E., Dejean de la Batie, G., Guyon, N., Mondoloni, S., Frangieh, J., Nguyen, C., Hardelin, J.-P., Marti, F., Corringer, P.-J., Faure, P., Mourot, A.. 2023-10-06. The interpeduncular nucleus blunts the rewarding effect of nicotine. https://doi.org/10.1101/2023.10.05.561018

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