Disruption of VGLUT1 in Cholinergic Medial Habenula Projections Increases Nicotine Self-Administration.
Autor: | Souter EA; Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093., Chen YC; Department of Neurobiology and Behavior sciences, University of California, Irvine, Irvine, CA 92697., Zell V; Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093., Lallai V; Department of Neurobiology and Behavior sciences, University of California, Irvine, Irvine, CA 92697., Steinkellner T; Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093., Conrad WS; Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093., Wisden W; Department of Life Sciences and UK Dementia Research Institute, Imperial College London, London SW7 2AZ, United Kingdom., Harris KD; Institute of Neurology, University College London, London WC1N 3BG, United Kingdom., Fowler CD; Department of Neurobiology and Behavior sciences, University of California, Irvine, Irvine, CA 92697., Hnasko TS; Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093 thnasko@health.ucsd.edu.; Research Service VA San Diego Healthcare System, San Diego, CA 92161. |
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Jazyk: | angličtina |
Zdroj: | ENeuro [eNeuro] 2022 Jan 10; Vol. 9 (1). Date of Electronic Publication: 2022 Jan 10 (Print Publication: 2022). |
DOI: | 10.1523/ENEURO.0481-21.2021 |
Abstrakt: | Cholinergic projections from the medial habenula (MHb) to the interpeduncular nucleus (IPN) have been studied for their complex contributions to nicotine addiction and have been implicated in nicotine reinforcement, aversion, and withdrawal. While it has been established that MHb cholinergic projections corelease glutamate, no direct evidence has demonstrated a role for this glutamate projection in nicotine consumption. In the present study, a novel floxed Slc17a7 [vesicular glutamate transporter 1 (VGLUT1)] mouse was generated and used to create conditional knock-out (cKO) mice that lack VGLUT1 in MHb cholinergic neurons. Loss of Slc17a7 expression in ventral MHb cholinergic neurons was validated using fluorescent in situ hybridization, and immunohistochemistry was used to demonstrate a corresponding reduction of VGLUT1 protein in cholinergic terminals in the IPN. We also used optogenetics-assisted electrophysiology to evoke EPSCs in IPN and observed a reduction of glutamatergic currents in the cKO, supporting the functional disruption of VGLUT1 in MHb to IPN synapses. cKO mice exhibited no gross phenotypic abnormalities and displayed normal thigmotaxis and locomotor behavior in the open-field assay. When trained to lever press for food, there was no difference between control and cKO. However, when tested in a nicotine self-administration procedure, we found that the loss of VGLUT1-mediated glutamate corelease led to increased responding for nicotine. These findings indicate that glutamate corelease from ventral MHb cholinergic neurons opposes nicotine self-administration, and provide additional support for targeting this synapse to develop potential treatments for nicotine addiction. (Copyright © 2022 Souter et al.) |
Databáze: | MEDLINE |
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