Ethanol intake patterns in female mice: Influence of allopregnanolone and the inhibition of its synthesis

Abstract

The neurosteroid allopregnanolone (ALLO) is a positive modulator of GABA(A) receptors that exhibits a psychopharmacological profile similar to ethanol (i.e., anxiolytic, sedative-hypnotic). Based on research suggesting that manipulation of ALLO levels altered ethanol self-administration in male rodents, the current studies determined whether exogenous ALLO administration or the inhibition of its synthesis in vivo modulated ethanol intake patterns in female C57BL/6J mice. Lickometer circuits collected temporal lick records of ethanol (10%, v/v) and water consumption during daily 2h limited access sessions. Following the establishment of stable ethanol intake, studies examined the effect of an acute ALLO challenge (3.2-24.0 mg/kg) or a 7-day blockade of ALLO production with finasteride (FIN; 50 or 100 mg/kg) on ethanol intake in a within-subjects design. In contrast to results in male mice, ethanol dose (g/kg), ethanol preference and most of the bout parameters were unaltered by ALLO pretreatment in female mice. Ethanol intake in females also was recalcitrant to 7-day treatment with 50 mg/kg FIN, whereas 100 mg/kg FIN significantly reduced the ethanol dose consumed by 35%. The FIN-attenuated ethanol intake was attributable to a significant decrease in bout frequency (up to 45%), with lick patterns indicating reduced maintenance of consumption throughout the 2-h session. FIN also produced a dose-dependent decrease in brain ALLO levels. In conjunction with data in male mice, the present findings indicate that there are sex differences in the physiological regulation of ethanol intake patterns by GABAergic neurosteroids.

Preclinical development of moxidectin as a novel therapeutic for alcohol use disorder

“…In addition, we also utilized a saline-treated control group in both of the 5-day investigations using female mice (24-h-bottle-bottle-choice and DID studies), it is unlikely that the differences in 10E and 20E intake between the MOX and saline group could be attributed to the estrous cycle. This conclusion is similar to previous work where no systematic changes in ethanol intake across weeks of baseline consumption in female C57BL/6 mice were observed (Ford et al, 2008). Collectively, these results suggests that the estrous cycle is unlikely to have an impact on the anti-alcohol effects of MOX and further supports the utility of MOX as a pharmacotherapy for AUD in both male and female.…”

The Impact of Gonadectomy and Adrenalectomy on Acute Withdrawal Severity in Male and Female C57BL/6J and DBA/2J Mice Following a Single High Dose of Ethanol

“…It has been shown that sensitivity to neuroactive steroids differs between genotypes in male B6 and D2 mice (Finn et al, 1997(Finn et al, , 2000, but this effect has not been investigated systematically in female animals. However, it has been shown that there is an increase in whole brain ALLO levels in male B6 mice in response to a voluntary drinking paradigm, while the same paradigm elicited no change in brain ALLO levels in female B6 mice (Finn et al, 2004b) and that injections of ALLO increased EtOH consumption in male B6 mice (Ford et al, 2005;Sinnott et al, 2002), but had no effect on consumption in female B6 mice (Ford et al, 2007). Taken together, these data suggest that female B6 mice may be relatively insensitive to neuroactive steroid modulation.…”

Null Mutation of 5α-Reductase Type I Gene Alters Ethanol Consumption Patterns in a Sex-Dependent Manner

“…Recent work with ganaxolone, a synthetic derivative of ALLO that exhibits metabolic resistance, reported a similar bimodal influence of this neurosteroid on operant ethanol self-administration in male alcohol preferring (P) rats (Besheer et al 2010). Curiously, female C57BL/6J mice were unresponsive to these modulatory effects of ALLO on limited access drinking in a procedure identical to that reported for C57BL/6J males (Ford et al 2008a; also see Finn et al 2010). Second, treatment with finasteride dose-dependently attenuated the acquisition (Ford et al 2008b) and the maintenance (Ford et al 2005a) of limited access ethanol intake in male mice, but a much higher dose was required to decrease ethanol drinking in female mice.…”

“…Second, treatment with finasteride dose-dependently attenuated the acquisition (Ford et al 2008b) and the maintenance (Ford et al 2005a) of limited access ethanol intake in male mice, but a much higher dose was required to decrease ethanol drinking in female mice. It was notable that the finasteride-induced decrease in ethanol intake was due to a sex-specific mechanism of drinking pattern alteration (Ford et al 2005a, 2008a; also see Finn et al 2010). Third, ALLO and ganaxolone facilitated reinstatement of ethanol seeking (Finn et al 2008; Nie and Janak 2003; Ramaker et al 2014) and ALLO as well as other GABA A R-positive modulatory steroids, including pregnanolone and allotetrahydrodeoxycorticosterone, substituted for the discriminative stimulus effects of ethanol (Grant et al 1996, 1997; Bowen et al 1999; Hodge et al 2001).…”

“…Further, earlier findings following pretreatment with ALLO (Ford et al 2005b, 2007) and finasteride (Ford et al 2005a, 2008a, b) to mice indicated that the onset of ethanol drinking in limited access ethanol consumption would be particularly sensitive to Srd5a1 deletion, and so latency to first bout and licking that occurred in the initial 20-min of access were given particular attention.…”