Glucocorticoid Receptor Antagonist Mifepristone Does Not Alter Innate Anxiety-Like Behavior in Genetically-Selected Marchigian Sardinian (msP) Rats

Abstract

Marchigian Sardinian alcohol-preferring (msP) rats serve as a unique model of heightened alcohol preference and anxiety disorders. Their innate enhanced stress and poor stress-coping strategies are driven by a genetic polymorphism of the corticotropin-releasing factor receptor 1 (CRF1) in brain areas involved in glucocorticoid signaling. The activation of glucocorticoid receptors (GRs) regulates the stress response, making GRs a candidate target to treat stress and anxiety. Here, we examined whether mifepristone, a GR antagonist known to reduce alcohol drinking in dependent rats, decreases innate symptoms of anxiety in msPs. Male and female msPs were compared to non-selected Wistar counterparts across three separate behavioral tests. We assessed anxiety-like behavior via the novelty-induced hypophagia (NIH) assay. Since sleep disturbances and hyperarousal are common features of stress-related disorders, we measured sleeping patterns using the comprehensive lab monitoring system (CLAMS) and stress sensitivity using acoustic startle measures. Rats received an acute administration of vehicle or mifepristone (60 mg/kg) 90 min prior to testing on NIH, acoustic startle response, and CLAMS. Our results revealed that both male and female msPs display greater anxiety-like behaviors as well as enhanced acoustic startle responses compared to Wistar counterparts. Male msPs also displayed reduced sleeping bout duration versus Wistars, and female msPs displayed greater acoustic startle responses versus male msPs. Importantly, the enhanced anxiety-like behavior and startle responses were not reduced by mifepristone. Together, these findings suggest that increased expression of stress-related behaviors in msPs are not solely mediated by acute activation of GRs.

Mifepristone as a pharmacological intervention for stress‐induced alcohol craving: A human laboratory study

“…Case in point, Marchigian Sardinian alcohol preferring (msP) rats (a genetically selected rat model of AUD with phenotypic trait resembling anxiety and stress-related disorders such as PTSD) were less responsive to mifepristone's ability to reduce alcohol self-administration 78 or anxiety-like behaviour and startle responses. 79 Our results are also consistent with the previous baboon study where mifepristone did not reduce alcohol consumption, 18 supporting the hypothesis that in an individual with severe AUD who consumes large amounts of alcohol, mifepristone pharmacokinetics may be non-linear. In summary, given (1) the floor effect during the alcohol self-administration in the bar laboratory; (2) the unlikely ability that naturalistic drinking may be changed in an AUD population of non-treatment seekers; (3) the known differences between treatment-seekers versus non-treatment seekers for AUD 80 ; (4) the fact that, unlike in our study, previous work 14 reported an effect of mifepristone in reducing alcohol drinking in people with AUD; and…”

“…The lack of mifepristone effect during the naturalistic drinking (outpatient setting) could be due to our sample being individuals with high family history of AUD and history of early trauma. Case in point, Marchigian Sardinian alcohol preferring (msP) rats (a genetically selected rat model of AUD with phenotypic trait resembling anxiety and stress‐related disorders such as PTSD) were less responsive to mifepristone's ability to reduce alcohol self‐administration 78 or anxiety‐like behaviour and startle responses 79 . Our results are also consistent with the previous baboon study where mifepristone did not reduce alcohol consumption, 18 supporting the hypothesis that in an individual with severe AUD who consumes large amounts of alcohol, mifepristone pharmacokinetics may be non‐linear.…”

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 ).…”

Sexually dimorphic effects of monoacylglycerol lipase inhibitor MJN110 on stress‐related behaviour and drinking in Marchigian Sardinian alcohol‐preferring rats

“…Anxiety-like behaviour was assessed using novelty-induced hypophagia (NIH) procedures as previously described (Vozella et al, 2021).…”