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GABA release from central amygdala neurotensin neurons differentially modulates ethanol consumption in male and female mice

Neuropsychopharmacology (2024)Cite this article

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Abstract

The central nucleus of the amygdala is known to play key roles in alcohol use and affect. Neurotensin neurons in the central nucleus of the amygdala have been shown to regulate alcohol drinking in male mice. However, little is known about which neurotransmitters released by these cells drive alcohol consumption or whether these cells drive alcohol consumption in female mice. Here we show that knockdown of GABA release from central amygdala neurotensin neurons using a Nts-cre-dependent vGAT-shRNA-based AAV strategy reduces alcohol drinking in male, but not female, mice. This manipulation did not impact avoidance behavior, except in a fasted novelty-suppressed feeding test, in which vGAT shRNA mice demonstrated increased latency to feed on a familiar high-value food reward, an effect driven by male mice. In contrast, vGAT shRNA female mice showed heightened sensitivity to thermal stimulation. These data show a role for GABA release from central amygdala neurotensin neurons in modulating consumption of rewarding substances in different motivational states.

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Fig. 1: Electrophysiolgoical validation of vGAT shRNA-induced reduction of GABA release from CeANts neurons.
Fig. 2: Knockdown of vGAT in NTSCeA neurons decreases alcohol drinking in an IA paradigm in male mice.
Fig. 3: vGAT knockdown in CeANts neurons increases thermal nociception without altering other mechanosensory behaviors.
Fig. 4: vGAT knockdown in CeANts neurons or ablation of these neurons does not modulate avoidance behavior.
Fig. 5: vGAT knockdown in CeANts neurons increases latency to feed in the novelty suppressed feeding test without altering novel object preference.

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Acknowledgements

The authors thank Drs. Robert Messing, for the AAV8-hSyn-FLEX-GFP-shvGAT virus.

Funding

Funded by NIAAA R01 AA026363 (ZAM), NIAAA U01 AA020911 (ZAM and TLK), and NINDS R01 NS122230 (TLK).

Author information

Author notes

  1. These authors contributed equally: Graydon B. Gereau, María L. Torruella-Suárez.

Authors and Affiliations

  1. Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Graydon B. Gereau, María L. Torruella-Suárez, Sarah E. Sizer, Mengfan Xia, Diana Zhou, Luke A. Wykoff, Adonay T. Teklezghi, Ali Alvarez-Pamir, Kristen M. Boyt, Thomas L. Kash & Zoé A. McElligott

  2. Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Graydon B. Gereau, Thomas L. Kash & Zoé A. McElligott

  3. Graduate Program in Neuroscience, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    María L. Torruella-Suárez

  4. Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Zoé A. McElligott

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Contributions

GBG, MLTS, ZAM, and TLK designed the research. MLTS did surgeries and drinking studies. GBG did surgeries and behavioral assays. MX, KMB, and GBG did sensory studies. SES did electrophysiology. GBG, DZ, LAW, AAP, ATT perfused mice and used microscopy to validate viral targeting and function. DZ scored novel object recognition test. GBG and ZAM wrote the paper with contributions from MLTS, SES, and MX.

Corresponding author

Correspondence to Zoé A. McElligott.

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Competing interests

ZAM is subcontracted by Epicypher on a project unrelated to this work DA057749. The other authors have nothing to disclose.

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Gereau, G.B., Torruella-Suárez, M.L., Sizer, S.E. et al. GABA release from central amygdala neurotensin neurons differentially modulates ethanol consumption in male and female mice. Neuropsychopharmacol. (2024). https://doi.org/10.1038/s41386-024-01830-5

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