Effect of Glucocorticoid Receptor Antagonism on Alcohol Self-Administration in Genetically-Selected Marchigian Sardinian Alcohol-Preferring and Non-Preferring Wistar Rats

Abstract

Alcoholism is a chronically relapsing disorder characterized by high alcohol intake and a negative emotional state during abstinence, which contributes to excessive drinking and susceptibility to relapse. Stress, dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis and alterations in glucocorticoid receptor (GR) function have been linked to transition from recreational consumption to alcohol use disorder (AUD). Here, we investigated the effect of pharmacological antagonisms of GR on alcohol self-administration (SA) using male and female Wistar and Marchigian Sardinian alcohol-preferring (msP) rats, a rodent line genetically selected for excessive alcohol drinking and highly sensitive to stress. Animals were trained to self-administer 10% (v/v) alcohol. Once a stable alcohol SA baseline was reached, we tested the effect of the GR antagonists mifepristone (0.0, 10, 30 and 60 mg/kg; i.p.) and CORT113176 (0.0, 10, 30 and 60 mg/kg) on alcohol SA. To evaluate whether the effects of the two compounds were specific for alcohol, the two drugs were tested on a similar saccharin SA regimen. Finally, basal blood corticosterone (CORT) levels before and after alcohol SA were determined. Systemic injection with mifepristone dose-dependently reduced alcohol SA in male and female Wistars but not in msPs. Administration of CORT113176 decreased alcohol SA in male and female Wistars as well as in female msPs but not in male msP rats. At the highest dose, mifepristone also reduced saccharin SA in male Wistars and female msPs, suggesting the occurrence of some nonspecific effects at 60 mg/kg of the drug. Similarly, the highest dose of CORT113176 (60 mg/kg) decreased saccharin intake in male Wistars. Analysis of CORT levels revealed that females of both rat lines had higher blood levels of CORT compared to males. Alcohol consumption reduced CORT in females but not in males. Overall, these findings indicate that selective blockade of GR selectively reduces alcohol SA, and genetically selected msP rats are less sensitive to this pharmacological manipulation compared to heterogeneous Wistars. Moreover, results suggest sex differences in response to GR antagonism and the ability of alcohol to regulate GR transmission.

Corticosterone Levels and Glucocorticoid Receptor Gene Expression in High Drinking in the Dark Mice and Their Heterogeneous Stock (HS/NPT) Founder Line

“…Glucocorticoids and GR have been shown to be important regulators of alcohol intake across species ( Koenig and Olive, 2004 ; Junghanns et al, 2005 ; Vendruscolo et al, 2012 , 2015 ; Repunte-Canonigo et al, 2015 ; Blaine et al, 2019 ; Jimenez et al, 2020 ; Savarese et al, 2020 ; Benvenuti et al, 2021 ; McGinn et al, 2021 ). Recently GR antagonism was shown to reduce ethanol intake in the selectively bred HDID-1 mice, but not in their founders HS/NPT, suggesting that selective breeding for high BALs enhanced sensitivity to GR antagonism, a finding that may have important implications for the genetic determinants of high-risk ethanol intake ( Savarese et al, 2020 ).…”

“…These dynamic changes in GR expression may contribute to the elevated alcohol intake observed with chronic alcohol use and dependence. Indeed, pharmacological antagonism of GR has been shown to reduce alcohol intake in rodents, non-human primates, and humans, across a range of drinking paradigms and access periods ( Koenig and Olive, 2004 ; Vendruscolo et al, 2012 , 2015 ; Repunte-Canonigo et al, 2015 ; Jimenez et al, 2020 ; Savarese et al, 2020 ; Benvenuti et al, 2021 ; McGinn et al, 2021 ), suggesting that GR activation promotes alcohol intake. Genetic studies also support a role for GR in risk for AUD.…”

Mifepristone as a pharmacological intervention for stress-Induced alcohol craving: a translational crossover randomized trial

“…The copyright holder for this preprint this version posted January 4, 2023. ; https://doi.org/10.1101/2023.01.02.23284122 doi: medRxiv preprint ability to reduce alcohol self-administration 19 . This information when translated in human laboratory study may inform pharmacotherapy approached based on family contribution to the development of AUD 20 .…”

Alcohol dependence and withdrawal increase sensitivity of central amygdalar GABAergic synapses to the glucocorticoid receptor antagonist mifepristone in male rats

“…This greater efficacy of mifepristone in dependent rats is in line with previous studies likely reflecting increased CeA GR function in alcohol dependence and protracted withdrawal ( Vendruscolo et al, 2015 ). Indeed, mifepristone has been shown to be most efficacious in reducing excessive alcohol drinking in animal models of binge-like drinking, heavy drinking, and alcohol dependence all of which are strong stressors per se while mixed effects of mifepristone on alcohol consumption or anxiety-related behaviors in non-dependent animals as well as in strains genetically-selected for innate high anxiety levels such as the Marchigian Sardinian rats have been reported ( Benvenuti et al, 2021 ; Calvo and Volosin, 2001 ; Fahlke et al, 1995 ; Holtyn and Weerts, 2019 ; Jacquot et al, 2008 ; Koenig and Olive, 2004 ; Newman et al, 2018 ; O’Callaghan et al, 2005 ; Ostroumov et al, 2016 ; Repunte-Canonigo et al, 2015 ; Savarese et al, 2020 ; Simms et al, 2012 ; Vendruscolo et al, 2015 ; Vendruscolo et al, 2012 ; Vozella et al, 2021 ; Yang et al, 2008 ).…”