AI Article Synopsis
- The study found that while CRF1 antagonists show promise in preclinical settings for reducing alcohol consumption, clinical trials have not produced similar results in humans with alcohol use disorder (AUD).
- Confounding factors include differences in study design, such as the use of experimenter-administered alcohol and a lack of female subject representation, which may limit the applicability of preclinical findings.
- The research revealed that chronic voluntary alcohol drinking led to changes in CRF1+ neurons that affected how these neurons respond to alcohol, with noticeable differences in response between male and female mice, suggesting potential reasons for the different efficacy of CRF1 antagonists in treating AUD in women.
Article Abstract
Despite strong preclinical evidence for the ability of corticotropin releasing factor 1 (CRF1) antagonists to regulate alcohol consumption, clinical trials have not yet demonstrated therapeutic effects of these compounds in alcohol use disorder (AUD) patients. Several confounding factors may limit the translation of preclinical CRF1 research to patients, including reliance on experimenter-administered alcohol instead of voluntary consumption, a preponderance of evidence collected in male subjects only and an inability to assess the effects of alcohol on specific brain circuits. A population of particular interest is the CRF1-containing neurons of the central amygdala (CeA). CRF1 CeA neurons are sensitive to ethanol, but the effects of alcohol drinking on CRF signalling within this population are unknown. In the present study, we assessed the effects of voluntary alcohol drinking on inhibitory control of CRF1+ CeA neurons from male and female CRF1:GFP mice using ex vivo electrophysiology and determined the contributions of CRF1 signalling to inhibitory control and voluntary alcohol drinking. Chronic alcohol drinking produced neuroadaptations in CRF1+ neurons that increased the sensitivity of GABA receptor-mediated sIPSCs to the acute effects of alcohol, CRF and the CRF1 antagonist R121919, but these adaptations were more pronounced in male versus female mice. The CRF1 antagonist CP-154,526 reduced voluntary alcohol drinking in both sexes and abolished sex differences in alcohol drinking. The lack of alcohol-induced adaptation in the female CRF1 system may be related to the elevated alcohol intake exhibited by female mice and could contribute to the ineffectiveness of CRF1 antagonists in female AUD patients.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8636550 | PMC |
| http://dx.doi.org/10.1111/adb.13067 | DOI Listing |
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