Souter, EA;
Chen, Y-C;
Zell, V;
Lallai, V;
Steinkellner, T;
Conrad, WS;
Wisden, W;
... Hnasko, TS; + view all
(2021)
Disruption of VGLUT1 in cholinergic medial habenula projections increases nicotine self-administration.
eNeuro
10.1523/ENEURO.0481-21.2021.
(In press).
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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 co-release glutamate, no direct evidence has demonstrated a role for this glutamate projection in nicotine consumption. In the present study, a novel floxed Slc17a7 (VGLUT1) mouse was generated and used to create conditional knockout (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 excitatory post-synaptic currents 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 co-release led to increased responding for nicotine. These findings indicate that glutamate co-release from ventral MHb cholinergic neurons opposes nicotine self-administration, and provide additional support for targeting this synapse to develop potential treatments for nicotine addiction.
| Type: | Article |
|---|---|
| Title: | Disruption of VGLUT1 in cholinergic medial habenula projections increases nicotine self-administration |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1523/ENEURO.0481-21.2021 |
| Publisher version: | https://doi.org/10.1523/ENEURO.0481-21.2021 |
| Language: | English |
| Additional information: | This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license, which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed. |
| Keywords: | acetylcholine (ACh, co-releas, glutamat, interpeduncular nucleus (IPN, medial habenula (MHb, nicotine |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Department of Neuromuscular Diseases |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10140875 |
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