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

AI Article Synopsis

  • Research on cholinergic projections from the medial habenula (MHb) to the interpeduncular nucleus (IPN) reveals their role in nicotine addiction, including reinforcement and withdrawal.
  • A new study used a conditional knock-out mouse model that lacked the vesicular glutamate transporter 1 (VGLUT1) specifically in MHb cholinergic neurons to investigate the impact on nicotine consumption.
  • The findings showed that the absence of VGLUT1 led to increased nicotine-seeking behavior, highlighting the importance of glutamate release in regulating nicotine self-administration and suggesting potential targets for addiction treatment.

Article Abstract

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 [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 expression in ventral MHb cholinergic neurons was validated using fluorescent 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.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8751853PMC
http://dx.doi.org/10.1523/ENEURO.0481-21.2021DOI Listing

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