The mineralocorticoid receptor antagonist spironolactone reduces alcohol self-administration in female and male rats

Abstract

Cortisol/corticosterone and the hypothalamic-pituitary-adrenal (HPA) axis serve an important role in modulating alcohol drinking behaviors. To date most alcohol research has focused on the functional involvement of corticosterone and the glucocorticoid receptor (GR), the primary receptor for corticosterone. Recent studies have indicated that the related mineralocorticoid receptor (MR), which binds both corticosterone and aldosterone, may also play a role in alcohol drinking. Therefore, the purpose of the present study was to test the functional role of MR signaling in alcohol self-administration via pharmacological antagonism of the MR with spironolactone. Male and female Long-Evans rats were trained to self-administer a sweetened alcohol solution (15% (v/v) alcohol +2% (w/v) sucrose). The effects of spironolactone (0, 10, 25, 50 mg/kg; IP) were tested on alcohol self-administration and under "probe extinction" conditions to measure the persistence of responding in the absence of the alcohol reinforcer. Parallel experiments in sucrose self-administration trained rats were used to confirm the specificity of spironolactone effects to an alcohol reinforcer. In female rats spironolactone (50 mg/kg) reduced alcohol self-administration and persistence of alcohol responding. In male rats spironolactone (25 and 50 mg/kg) reduced alcohol self-administration, but not persistence of alcohol responding. Spironolactone reduced sucrose intake in female rats only, and locomotion in male and female rats during sucrose self-administration. There was no effect of spironolactone on persistence of sucrose responding. These studies add to growing evidence that the MR is involved in alcohol drinking, while underscoring the importance of studying both male and female animals.

Central amygdala mineralocorticoid receptors modulate alcohol self-administration

“…Male rhesus macaques and Wistar rats with alcohol experience showed inverse correlations between central amygdala (CeA) MR expression and measures of alcohol drinking, while human AUD patients showed correlations between circulating aldosterone and alcohol craving (Aoun et al, 2018). Our previous findings built upon this study and demonstrated that the MR antagonist spironolactone, an FDA approved drug indicated for managing hypertension, reduced alcohol self-administration and response persistence in male and female rats (Makhijani et al, 2018). Together, these studies have begun to outline a relationship between MR and alcohol drinking; however, the functional role of CeA MR in alcohol drinking is not fully understood and it is unknown if altering CeA MR expression would alter alcohol drinking.…”

“…Female rats were used for all self-administration studies. Our previous studies reported similar effects of MR antagonism on alcohol self-administration between sexes (Makhijani et al, 2018). In Experiments 1 and 2 rats were single-housed throughout the study, in Experiments 3 and 4 rats were double-housed until surgery and then single-housed through the rest of the study.…”

“…As MR regulate basal levels of the hormone corticosterone (Joels and de Kloet, 2017) which is known to modulate alcohol self-administration (Fahlke et al, 1994a, Fahlke et al, 1994b, we hypothesized that the observed reduction in alcohol selfadministration following spironolactone pretreatment (Makhijani et al, 2018) was due to stimulation of the HPA axis by inhibition of glucocorticoid negative feedback (Atkinson et al, 2008). Indeed, systemic administration of spironolactone (50 mg/kg) increased plasma corticosterone similar to other MR antagonists (Ratka et al, 1989, Bitran et al, 1998.…”

“…Rats were trained to self-administer a 20% (v/v) alcohol solution (20A) on a fixed ratio 2 (FR2) reinforcement schedule across 30-minute sessions, five days a week (M-F) via sucrose fading as described in (Makhijani et al, 2018, Randall et al, 2017. Sucrose fading began with self-administration of 2% alcohol/10% (w/v) sucrose (2A/10S), then 5A/10S, 10A/10S, 10A/5S, 15A/5S, 15A/2S, and 20A/2S on subsequent sessions, ending with 20A which remained the reinforcer through the remainder of the study.…”

“…Following establishment of stable alcohol self-administration (approximately 40 sessions), rats (n = 18/group) received spironolactone (0, 50 mg/kg; IP; 1 mL/kg) 30 minutes prior to an alcohol self-administration session. We have previously demonstrated that this dose of spironolactone reduces alcohol self-administration in male and female rats (Makhijani et al, 2018). Immediately after the 30-min selfadministration, blood was collected for analysis of plasma corticosterone as described above.…”