Sigma-1 antagonism inhibits binge ethanol drinking at adolescence

Highlights

• We assessed effects of the S1-R antagonists S1RA or BD-1063 on ethanol drinking.

• S1RA blocked ethanol binge drinking in male and female adolescent Wistar rats.

• BD-1063 blocked ethanol binge drinking in male and female adolescent Wistar rats.

• S1RA reduced free-choice ethanol drinking long after its clearance.

• S1-R antagonists are promising targets for the development of new medications.

Abstract

Background

Ethanol use during adolescence is a significant health problem, yet the pharmacological treatments to reduce adolescent binge drinking are scarce. The present study assessed, in male and female adolescent Wistar rats, if the sigma-1 receptor (S1-R) antagonists S1RA or BD-1063 disrupted ethanol drinking.

Methods

Three times a week, for two weeks, the rats received the S1-R antagonists. Thirty min later they were exposed, for 2 h, to a bottle of 8% or 10 % v/v ethanol. A 24 h, two-bottle, ethanol intake test was conducted after termination of these procedures. A subset of these rats was tested for recognition memory via the novel object recognition test.

Results

The rats given 64 mg/kg S1RA drank, in each binge session, significantly less than vehicle counterparts. Male rats given 4 or 16 mg/kg S1RA drank significantly less than those given 0 mg/kg in session 3 or in session 1 and 2, respectively; whereas female rats given 4 or 16 mg/kg drank significantly less than females given 0 mg/kg in session 2–5 or in sessions 2–6, respectively. Administration of 32 mg/kg, but not of 2 or 8 mg/kg, BD-1063 suppressed, across sessions, ethanol drinking. S1-R antagonism reduced absolute ethanol drinking at the two-bottle choice post-test. Recognition memory was not affected by the ethanol exposure.

Conclusions

The results indicate that S1-R antagonists may be promising targets to prevent increases in ethanol intake at adolescence. The persistent effect of S1-R antagonism in free-choice drinking suggests that modulation of the S1-R is altering plastic effects associated with ethanol exposure.

Introduction

Recent studies have warned on the high prevalence of teenage drinking, the closing of the sex gap in ethanol consumption (Thibaut, 2018), and the rising occurrence of adolescent binge drinking (Pilatti et al., 2017; Spear, 2018). The latter is associated with immediate (Wicki et al., 2018) or long-term negative consequences, including greater likelihood of exhibiting an alcohol use disorder (AUD) (Rial Boubeta et al., 2018).

Sigma receptors, of which two subtypes (sigma-1 and sigma-2) have been described, were first proposed as new opioid receptors, and they were also confused with PCP/NMDA receptors (Maurice and Su, 2009). The endogenous ligand of sigma receptors is still unknown, although some neurosteroids have been suggested as likely candidates (Hayashi and Su, 2005). The sigma-1 receptor (S1-R) is an intracellular chaperone with an aminoacidic sequence well conserved across species (Alon et al., 2017; Maurice and Su, 2009); and is concentrated in brain areas related to motivation, learning and sensorimotor processes, including hippocampus, olfactory bulb, and substantia nigra (Cobos et al., 2008). The S1-R ligands have long been expected to mitigate neurodegenerative and mood disorders, chronic pain or drug abuse, among other diseases (Merlos et al., 2017; Romero and Portillo-Salido, 2019). Systemic or intracerebroventricular administration of a S1-R agonist (Bhutada et al., 2012; Maurice et al., 2003) enhances preference for a place associated with the effects of ethanol (Quadir et al., 2019). Moreover, S1-R agonism via DTG exacerbated operant responding for ethanol (Sabino et al., 2011; Valenza et al., 2020), an effect disrupted by BD-1063 (Sabino et al., 2011). On the other hand, it has been also shown that antagonism of S1-R, via administration of BD-1063/1047 or NE-100, dose-dependently inhibited ethanol-induced behavioral activation in an open field (Maurice et al., 2003) or ethanol self-administration (Blasio et al., 2015; Sabino et al., 2009b). Altogether, these studies suggest that antagonism of S1-R reduces ethanol seeking and intake, and hence is a promising strategy for the development of medications to treat risky drinking.

The density of S1-R levels is affected by the hormonal changes that take place at adolescence (Moradpour et al., 2016). This suggests that the effects of S1-R agonists can be age-specific. The modulatory effect of the S1-R system on ethanol intake during adolescence remains uncharted and, despite the suggestion for adequate sex representation (Hilderbrand and Lasek, 2018), all of the studies on the role of S1-R in ethanol consumption have employed males (Quadir et al., 2019). This is particularly troubling, as female rats (Varlinskaya et al., 2015; Vetter-O’Hagen et al., 2011) and mice (Lopez et al., 2011; Szumlinski et al., 2019) consistently exhibit greater ethanol intake and preference than males [for a comprehensive review, see (Roth et al., 2004)], and women tend to progress more rapidly from alcohol initiation or first drunkenness to problematic drinking (Brady and Randall, 1999; Erol and Karpyak, 2015). The present study assessed the role of the S1-R system on binge-like ethanol drinking in adolescent Wistar rats, both male and female. We evaluated if pretreatment with the S1-R antagonists S1RA or BD-1063 disrupted drinking in a procedure that induces levels of drinking akin to those found during a binge drinking episode (Salguero et al., 2020). It was possible that the binge exposure altered recognition memory (Marco et al., 2017), and that BD-1063 protected from this effect. This was assessed in Experiment 2, via the novel object recognition (NOR) test.