Disruption of VGLUT1 in Cholinergic Medial Habenula Projections Increases Nicotine Self-Administration.

Publisher: Society for Neuroscience Country of Publication: United States NLM ID: 101647362 Publication Model: Electronic-Print Cited Medium: Internet ISSN: 2373-2822 (Electronic) Linking ISSN: 23732822 NLM ISO Abbreviation: eNeuro Subsets: MEDLINE

Original Publication: [Washington, DC] : Society for Neuroscience, [2014]-

Habenula* ; Interpeduncular Nucleus*; Animals ; In Situ Hybridization, Fluorescence ; Mice ; Nicotine ; Nicotinic Agonists

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.)

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K99 AG059834 United States AG NIA NIH HHS; R01 DA036612 United States DA NIDA NIH HHS; R21 DA054693 United States DA NIDA NIH HHS; R01 DC009947 United States DC NIDCD NIH HHS; DP1 DA039658 United States DA NIDA NIH HHS; I01 BX003759 United States BX BLRD VA; K99 DA046514 United States DA NIDA NIH HHS

Keywords: acetylcholine; corelease; glutamate; interpeduncular nucleus; medial habenula; nicotine

0 (Nicotinic Agonists)
6M3C89ZY6R (Nicotine)

Date Created: 20211208 Date Completed: 20220202 Latest Revision: 20220716

20240513

PMC8751853

10.1523/ENEURO.0481-21.2021

34876472