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Peer-reviewedCC BY-NC-NDMolecular Psychiatry

Alcohol abstinence precipitates alcohol seeking and aversion-resistant intake in association with increased BNST activity

  • Marie A. Doyle1,2,3
  • Hye Jean Yoon4,5
  • Megan E. Altemus5
  • Anika S. Park5
  • Martha E. Troutman5,6
  • Laura Grunenkovaite1,3
  • Danielle N. Adank1,3,5
  • Caitlyn M. Edwards1,2,3,5
  • Nia A. Chetkovich5
  • Sabrina D. Hallal1,3
  • Louise Lantier6
  • Cody A. Siciliano4,5
2 more authors
  • Erin S. Calipari4,5
  • Danny G. Winder7,8,9,10
10 affiliations
  1. 1Brudnick Neuropsychiatric Research Institute, UMass Chan Medical School, Worcester, MA, USA
  2. 2Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA
  3. 3Department of Neurobiology, UMass Chan Medical School, Worcester, MA, USA
  4. 4Dept. of Pharmacology, Vanderbilt University, Nashville, TN, USA
  5. 5Vanderbilt Center for Addiction Research, Vanderbilt University, Nashville, TN, USA
  6. 6Vanderbilt Mouse Metabolic Phenotyping Center, Vanderbilt University, Nashville, TN, USA
  7. 7Brudnick Neuropsychiatric Research Institute, UMass Chan Medical School, Worcester, MA, USA. [email protected]
  8. 8Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA. [email protected]
  9. 9Department of Neurobiology, UMass Chan Medical School, Worcester, MA, USA. [email protected]
  10. 10Vanderbilt Center for Addiction Research, Vanderbilt University, Nashville, TN, USA. [email protected]
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Abstract

Alcohol Use Disorder (AUD) is defined by a common diagnostic framework, yet individuals show diverse drinking patterns and relapse vulnerabilities during abstinence, reflecting neurobiological heterogeneity. The bed nucleus of the stria terminalis (BNST) is well positioned to contribute to this variability. To understand how BNST activity co-segregates with individual alcohol behavior trajectories, we used the Structured Tracking of Alcohol Reinforcement (STAR) operant task to phenotype C57BL/6J mice as high, low, or aversion-resistant ethanol drinkers. During initial self-administration, dBNST cFos+ counts correlated with intake, linking dBNST activation to operant drinking. Using in vivo fiber photometry, we found that aversion-resistant drinkers displayed elevated dBNST calcium transients during drinking bouts despite similar intake across groups, consistent with heightened dBNST recruitment. Forced abstinence uncovered prominent phenotype-specific adaptations, where ethanol seeking during protracted, but not early, abstinence predicted aversion-resistant intake. High and low drinkers reduced seeking behavior across abstinence, whereas aversion-resistant drinkers persisted. Consistently, dBNST calcium transients increased during protracted abstinence seeking only in aversion-resistant drinkers, highlighting phenotype-specific plasticity. Comparing mice exposed to abstinence versus only operant training showed that abstinence itself potentiates aversion-resistant intake. Finally, these dBNST dynamics were ethanol-specific, as saccharin drinking more closely reflected activity for high drinkers. Together, these findings reveal that ethanol abstinence precipitates ethanol seeking and aversion-resistant intake, associated with phenotypic dBNST calcium dynamics. Because causality was not established, future studies are needed to define mechanistic contributions of dBNST activity to phenotypic behaviors. By uncovering how dBNST activity adapts in aversion-resistant drinkers, this work offers insight into AUD heterogeneity.

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Cite

BibTeXRIS
BibTeX
@article{doyle2026alcohol,
  title = {{Alcohol abstinence precipitates alcohol seeking and aversion-resistant intake in association with increased BNST activity}},
  author = {Marie A. Doyle and Hye Jean Yoon and Megan E. Altemus and Anika S. Park and Martha E. Troutman and Laura Grunenkovaite and Danielle N. Adank and Caitlyn M. Edwards and Nia A. Chetkovich and Sabrina D. Hallal and Louise Lantier and Cody A. Siciliano and Erin S. Calipari and Danny G. Winder},
  journal = {Molecular Psychiatry},
  year = {2026},
  month = jun,
  doi = {10.1038/s41380-026-03660-x},
  url = {https://doi.org/10.1038/s41380-026-03660-x},
  note = {CC BY-NC-ND},
}
RIS
TY  - JOUR
TI  - Alcohol abstinence precipitates alcohol seeking and aversion-resistant intake in association with increased BNST activity
AU  - Marie A. Doyle
AU  - Hye Jean Yoon
AU  - Megan E. Altemus
AU  - Anika S. Park
AU  - Martha E. Troutman
AU  - Laura Grunenkovaite
AU  - Danielle N. Adank
AU  - Caitlyn M. Edwards
AU  - Nia A. Chetkovich
AU  - Sabrina D. Hallal
AU  - Louise Lantier
AU  - Cody A. Siciliano
AU  - Erin S. Calipari
AU  - Danny G. Winder
PY  - 2026
DA  - 2026/06/03
JO  - Molecular Psychiatry
DO  - 10.1038/s41380-026-03660-x
UR  - https://doi.org/10.1038/s41380-026-03660-x
AB  - Alcohol Use Disorder (AUD) is defined by a common diagnostic framework, yet individuals show diverse drinking patterns and relapse vulnerabilities during abstinence, reflecting neurobiological heterogeneity. The bed nucleus of the stria terminalis (BNST) is well positioned to contribute to this variability. To understand how BNST activity co-segregates with individual alcohol behavior trajectories, we used the Structured Tracking of Alcohol Reinforcement (STAR) operant task to phenotype C57BL/6J mice as high, low, or aversion-resistant ethanol drinkers. During initial self-administration, dBNST cFos+ counts correlated with intake, linking dBNST activation to operant drinking. Using in vivo fiber photometry, we found that aversion-resistant drinkers displayed elevated dBNST calcium transients during drinking bouts despite similar intake across groups, consistent with heightened dBNST recruitment. Forced abstinence uncovered prominent phenotype-specific adaptations, where ethanol seeking during protracted, but not early, abstinence predicted aversion-resistant intake. High and low drinkers reduced seeking behavior across abstinence, whereas aversion-resistant drinkers persisted. Consistently, dBNST calcium transients increased during protracted abstinence seeking only in aversion-resistant drinkers, highlighting phenotype-specific plasticity. Comparing mice exposed to abstinence versus only operant training showed that abstinence itself potentiates aversion-resistant intake. Finally, these dBNST dynamics were ethanol-specific, as saccharin drinking more closely reflected activity for high drinkers. Together, these findings reveal that ethanol abstinence precipitates ethanol seeking and aversion-resistant intake, associated with phenotypic dBNST calcium dynamics. Because causality was not established, future studies are needed to define mechanistic contributions of dBNST activity to phenotypic behaviors. By uncovering how dBNST activity adapts in aversion-resistant drinkers, this work offers insight into AUD heterogeneity.
SN  - 1359-4184
SN  - 1476-5578
ER  -