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Central amygdala corticotropin-releasing factor neurons promote hyponeophagia but do not control alcohol drinking in mice

Molecular Psychiatry volume 27, pages 2502–2513 (2022)Cite this article

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Abstract

Corticotropin-releasing factor (CRF) signaling in the central nucleus of the amygdala (CeA) plays a critical role in rodent models of excessive alcohol drinking. However, the source of CRF acting in the CeA during alcohol withdrawal remains to be identified. In the present study, we hypothesized that CeA CRF interneurons may represent a behaviorally relevant source of CRF to the CeA increasing motivation for alcohol via negative reinforcement. We first observed that Crh mRNA expression in the anterior part of the mouse CeA correlates positively with alcohol intake in C57BL/6J males with a history of chronic binge drinking followed by abstinence and increases upon exposure to chronic intermittent ethanol (CIE) vapor inhalation. We then found that chemogenetic activation of CeA CRF neurons in Crh-IRES-Cre mouse brain slices increases gamma-aminobutyric acid (GABA) release in the medial CeA, in part via CRF1 receptor activation. While chemogenetic stimulation exacerbated novelty-induced feeding suppression (NSF) in alcohol-naïve mice, thereby mimicking the effect of withdrawal from CIE, it had no effect on voluntary alcohol consumption, following either acute or chronic manipulation. Furthermore, chemogenetic inhibition of CeA CRF neurons did not affect alcohol consumption or NSF in chronic alcohol drinkers exposed to air or CIE. Altogether, these findings indicate that CeA CRF neurons produce local release of GABA and CRF and promote hyponeophagia in naïve mice, but do not drive alcohol intake escalation or negative affect in CIE-withdrawn mice. The latter result contrasts with previous findings in rats and demonstrates species specificity of CRF circuit engagement in alcohol dependence.

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Fig. 1: Crh mRNA levels in the anterior CeA increase upon chronic intermittent alcohol exposure.
Fig. 2: Validation of Cre activity and chemogenetic stimulation in CeA CRF neurons of Crh-IRES-Cre mice.
Fig. 3: Chemogenetic stimulation of CeA CRF neurons increases GABA release onto medial CeA neurons in a CRF1-dependent manner.
Fig. 4: Chemogenetic stimulation of CeA CRF neurons does not affect alcohol drinking.
Fig. 5: Chemogenetic stimulation of CeA CRF neurons exacerbates hyponeophagia without altering other affective responses nor appetite.
Fig. 6: Chemogenetic inhibition of CeA CRF neurons does not reverse ethanol intake escalation or affective disturbance in alcohol-dependent mice.

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Acknowledgements

We wish to thank Sophia Zhu, Tanvi Shah, and Catherine Lopez for their assistance with brain slicing and immunohistochemistry, and Dr. Michal Bajo for his assistance with electrophysiological recordings. We are also grateful for the support of TSRI Alcohol Research Center Animal Models Core, which conducted blood ethanol concentration analysis for this study.

Funding

This work was supported by the following grants from the National Institutes of Health: AA024198 (CC), AA026685 (CC), AA027636 (CC), AA027372 (CC), AA006420 (CC and MR), AA021491 (MR), AA015566 (MR), AA023002 (MAH), and AA024952 (HS), as well as stipends from University of Benin, Benin City, Nigeria (AO) and Kingsefe Pharmacy, Benin City, Nigeria (AO). These funding sources were not involved in study design, data collection, analysis, interpretation, or decision to publish.

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  1. These authors contributed equally: Max Kreifeldt, Melissa A Herman, Harpreet Sidhu, Agbonlahor Okhuarobo.

Authors and Affiliations

  1. The Scripps Research Institute, Department of Molecular Medicine, La Jolla, CA, USA

    Max Kreifeldt, Melissa A. Herman, Harpreet Sidhu, Agbonlahor Okhuarobo, Giovana C. Macedo, Roxana Shahryari, Pauravi J. Gandhi, Marisa Roberto & Candice Contet

  2. Department of Pharmacology, Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, School of Medicine, Chapel Hill, NC, USA

    Melissa A. Herman

  3. University of Benin, Faculty of Pharmacy, Department of Pharmacology & Toxicology, Benin City, Nigeria

    Agbonlahor Okhuarobo

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MK: Investigation, Methodology, Validation. MAH: Conceptualization, Investigation, Formal analysis, Writing – review & editing. HS: Investigation, Methodology. AO: Investigation, Validation. GCM: Validation. RS: Validation. PJG: Validation. MR: Conceptualization, Writing – review & editing. CC: Conceptualization, Funding acquisition, Investigation, Validation, Formal analysis, Supervision, Writing – original draft.

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Kreifeldt, M., Herman, M.A., Sidhu, H. et al. Central amygdala corticotropin-releasing factor neurons promote hyponeophagia but do not control alcohol drinking in mice. Mol Psychiatry 27, 2502–2513 (2022). https://doi.org/10.1038/s41380-022-01496-9

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