Corticotropin-Releasing Factor Modulates Binge-Like Ethanol Drinking in a Sex-Dependent Manner: Impact of Amygdala Deletion and Inhibition of a Central Amygdala to Lateral Hypothalamus Circuit

Sophie C Bendrath; Hernán G Méndez; Anne M Dankert; Jose Manuel Lerma-Cabrera; Francisca Carvajal; Ana Paula S Dornellas; Sophia Lee; Sofia Neira; Harold Haun; Eric Delpire; Montserrat Navarro; Thomas L Kash; Todd E Thiele

doi:10.1016/j.bpsgos.2024.100405

Corticotropin-Releasing Factor Modulates Binge-Like Ethanol Drinking in a Sex-Dependent Manner: Impact of Amygdala Deletion and Inhibition of a Central Amygdala to Lateral Hypothalamus Circuit

Biol Psychiatry Glob Open Sci. 2024 Oct 25;5(1):100405. doi: 10.1016/j.bpsgos.2024.100405. eCollection 2025 Jan.

Authors

Sophie C Bendrath^{1

2}, Hernán G Méndez^{2

3}, Anne M Dankert^{1

2}, Jose Manuel Lerma-Cabrera⁴, Francisca Carvajal⁴, Ana Paula S Dornellas^{1

2}, Sophia Lee^{2

5}, Sofia Neira^{2

5}, Harold Haun^{2

5}, Eric Delpire⁶, Montserrat Navarro^{1

2}, Thomas L Kash^{1

2

5}, Todd E Thiele^{1

2}

Affiliations

¹ Department of Psychology and Neuroscience, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
² Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
³ Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
⁴ Department of Psychology, University of Almería, Almería, Spain.
⁵ Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
⁶ Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, Tennessee.

Abstract

Background: Binge alcohol drinking is a dangerous behavior that can contribute to the development of more severe alcohol use disorder. Importantly, the rate and severity of alcohol use disorder has historically differed between men and women, suggesting that there may be sex differences in the central mechanisms that modulate alcohol (ethanol) consumption. Corticotropin-releasing factor (CRF) is a centrally expressed neuropeptide that has been implicated in the modulation of binge-like ethanol intake, and emerging data highlight sex differences in CRF systems.

Methods: In the current report, we characterized CRF+ neurocircuitry arising from the central nucleus of the amygdala (CeA) and innervating the lateral hypothalamus (LH) in the modulation of binge-like ethanol intake in male and female mice.

Results: Using chemogenetic tools, we found that silencing the CRF+ CeA to LH circuit significantly blunted binge-like ethanol intake in male but not female mice. Consistently, genetic deletion of CRF from neurons of the CeA blunted ethanol intake exclusively in male mice. Furthermore, pharmacological blockade of the CRF₁ receptor in the LH significantly reduced binge-like ethanol intake in male mice only, while CRF₂ receptor activation in the LH failed to alter ethanol intake in either sex. Finally, a history of binge-like ethanol drinking reduced C rf messenger RNA levels in the CeA regardless of sex.

Conclusions: These observations provide novel evidence that CRF+ CeA to LH neurocircuitry is more sensitive for modulating binge-like ethanol intake in male mice, which may provide insight into the mechanisms that guide known sex differences in binge-like ethanol intake.

Keywords: Binge-like; Central amygdala; Chemogenetic; Corticotropin-releasing factor; Drinking in the dark; Ethanol; Lateral hypothalamus; Sex differences.

Plain language summary

Binge alcohol drinking is a dangerous behavior that can contribute to more severe alcohol use disorders, and central corticotropin-releasing factor (CRF) signaling has been identified as an important modulator of binge drinking. Here, Bendrath et al. identify a CRF+ circuit between the central amygdala and lateral hypothalamus, and by employing a combination of pharmacological, chemogenetic, and genetic approaches, they show that this CRF+ circuit is more sensitive to modulating binge drinking in male than in female mice.