Effects of Finasteride on Chronic and Acute Ethanol Withdrawal Severity in the WSP and WSR Selected Lines

Abstract

The neurosteroid allopregnanolone (ALLO) is a potent positive modulator of gamma-aminobutyric acidA (GABAA) receptors that can modulate ethanol (EtOH) withdrawal. The 5alpha-reductase inhibitor finasteride blocks the formation of ALLO from progesterone and was recently found to reduce certain effects of EtOH. Using the Withdrawal Seizure-Prone (WSP) and Withdrawal Seizure-Resistant (WSR) selected lines, in the present studies we examined the effect of finasteride on acute and chronic EtOH withdrawal severity. In the first two studies, male WSP and WSR mice were exposed to 72-hr EtOH vapor or air and received four injections of finasteride (50 mg/kg intraperitoneal (IP) or vehicle 24 hr before and each day of the vapor exposure. After removal from the inhalation chamber, mice were scored for handling-induced convulsions (HICs) hourly for 12 hr and then again at 24 hr (study 1) or were tested on the elevated plus maze at 24 hr after removal from the inhalation chamber (study 2). In the third experiment, mice were pretreated with finasteride or vehicle 24 hr before an acute dose of EtOH (4 g/kg ip) or saline and then were tested for HICs as in the chronic study. In both chronic EtOH studies, finasteride pretreatment reduced EtOH withdrawal severity, measured by HICs, and anxiety-related behavior, but only in the WSP selected line. However, finasteride pretreatment also significantly decreased blood EtOH concentration on the initiation of withdrawal in both chronic EtOH studies in WSP and WSR mice. In contrast, pretreatment with finasteride slightly enhanced acute EtOH withdrawal severity in WSP mice, whereas there was no effect of finasteride or EtOH injection on HICs in WSR mice. Collectively, these findings indicate that the WSP line is more sensitive than the WSR line to the modulatory effects of finasteride in terms of both chronic and acute EtOH withdrawal severity. The differential effect of finasteride on acute versus chronic EtOH withdrawal severity may result from an indirect effect of finasteride on EtOH pharmacokinetics in the chronic paradigm.