2025-09-30 ワシントン州立大学(WSU)
<関連情報>
- https://news.wsu.edu/press-release/2025/09/30/study-finds-altering-one-brain-area-could-rid-alcohol-withdrawal-symptoms/
- https://www.sciencedirect.com/science/article/pii/S002839082500303X
慢性アルコール曝露に対する小脳の適応を選択的に阻害すると、C57BL6/Nマウスの急性アルコール離脱症状の重症度が軽減される Selectively counteracting cerebellar adaptations to chronic alcohol exposure reduces acute alcohol withdrawal severity in C57BL6/N mice
Nadia A. McLean, Samantha N. Shippell Stiles, Aspen E. Harder, Chloe M. Erikson, Gloria J. Lee, Dominik Schnalzer, Margot Ernst, Marko D. Mihovilovic, Giuseppe Giannotti, David J. Rossi
Neuropharmacology Available online 19 July 2025
DOI:https://doi.org/10.1016/j.neuropharm.2025.110595
Graphical abstract
Highlights
- Adaptation of cerebellar GC inhibition mediates aversive EtOH withdrawal symptoms.
- GC specific inhibitory DREADDs improve motor discoordination during EtOH withdrawal.
- GC specific GABAAR enhancer improves negative emotionality during EtOH withdrawal.
- Cerebellum may be targeted to reduce negative reinforcement for EtOH consumption.
Abstract
A critical component of Alcohol Use Disorder (AUD) is alcohol (EtOH) withdrawal and consequent aversive withdrawal symptoms that generate negative reinforcement for renewed EtOH consumption to alleviate such symptoms. Here, we simulated human binge EtOH consumption and subsequent acute withdrawal by exposing male and female C57BL6/N mice to EtOH vapor for varying durations (24–72 h). During acute withdrawal, starting 4 h after removal from EtOH vapor, we used patch-clamp recording in cerebellar slices, combined with behavioral analysis of aversive somatic/motor (performance on the accelerating rotorod) and affective/emotional (ultrasonic vocalizations and blood corticosterone) withdrawal symptoms. We found that cerebellar granule cells (GCs) exhibit a homeostatic downregulation of sIPSC frequency that parallels development of motor discoordination and negative emotional affect, all starting at ∼48–72 h of EtOH vapor exposure. Fitting with the negative reinforcement component of the AUD cycle, re-exposure to EtOH during withdrawal reduced somatic and affective withdrawal symptoms. Importantly, selective chemogenetic inhibition of GCs during withdrawal improved motor coordination, likely via actions at the GC axon terminals, and selective pharmacological inhibition of GCs via enhancement of the tonic GABAAR current, using PZ-II-029 (Compound 6), significantly improved negative emotional affect. Collectively, these results indicate that cerebellar homeostatic adaptations mediate aspects of both somatic and affective aversive EtOH withdrawal symptoms, and that restoration of cerebellar adaptations can effectively treat such symptoms. Moreover, they highlight the cerebellum as a promising selective target for treating aversive EtOH withdrawal symptoms, a critical component of the AUD cycle.
