Sex-specific plasticity in CRF regulation of inhibitory control in central amygdala CRF1 neurons after chronic voluntary alcohol drinking.

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 GABAA 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.

Sex differences in corticotropin releasing factor peptide regulation of inhibitory control and excitability in central amygdala corticotropin releasing factor receptor 1-neurons.

The central amygdala (CeA) is a critical regulator of emotional behavior that has been implicated in psychiatric illnesses, including anxiety disorders and addiction. The CeA corticotropin releasing factor receptor 1 (CRF1) system has been implicated in alcohol use disorder (AUD) and mood disorders, and has been shown to regulate anxiety-like behavior and alcohol consumption in rodents. However, the effects of CRF signaling within the CRF receptor 1-containing (CRF1+) population of the CeA remain unclear, and the effects of ethanol and CRF1 manipulations in female rodents have not been assessed. Here, we characterized inhibitory control and CRF1 signaling in male and female CRF1-GFP reporter mice. Male and female CRF1+ CeA neurons exhibited similar baseline GABAergic signaling and excitability and were comparably sensitive to CRF-induced increases in presynaptic GABA release. CRF1 antagonism reduced GABA release onto CRF1-containing neurons comparably in both males and females. Acute ethanol application reduced GABA release onto CRF1+ neurons from males, but female CRF1+ neurons were insensitive to ethanol. Exogenous CRF increased the firing rate of CRF1-containing neurons to a greater extent in male cells versus female cells, and CRF1 antagonism reduced firing in females but not males. Together, these findings indicate a critical sex-specific role for the CRF system in regulating inhibitory control and excitability of CRF1-containing neurons in the central amygdala. Sex differences in sensitivity of CRF/CRF1 signaling provide useful context for the sex differences in psychiatric illness reported in human patients, particularly AUD.