Ethanol’s interaction with BK channel α subunit residue K361 does not mediate behavioral responses to alcohol in mice

Abstract

Large conductance potassium (BK) channels are among the most sensitive molecular targets of ethanol. Whether the action of ethanol at BK channels influences the motivation to drink alcohol remains to be determined. In the present study, we sought to investigate the behavioral relevance of this interaction by introducing in the mouse genome a point mutation (BK α K361N) known to render BK channels insensitive to ethanol while preserving their physiological function. We demonstrate that preventing ethanol′s interaction with BK channels at this site hinders the escalation of voluntary alcohol intake induced by repeated cycles of alcohol intoxication and withdrawal. In contrast, the mutation does not alter ethanol′s acute behavioral effects, nor the metabolic and activity changes induced by chronic exposure to alcohol. Our findings point at BK channel ethanol-sensing capacity as a vulnerability mechanism in the transition from moderate alcohol consumption to pathological patterns of alcohol abuse.

Influence of early‐life adversity on responses to acute and chronic ethanol in female mice

“…Furthermore, we did not test enough doses to fit a dose–response curve for ED 50 calculation, such that the antinociceptive potency of EtOH cannot be compared between CTL and LBN females. The fact that the antinociceptive effect of EtOH did not reach significance in the CTL females, while it did under identical testing conditions and comparable baseline thresholds in C57BL/6J males (Okhuarobo, Kreifeldt, et al, 2020) suggests that C57BL/6J females may be less sensitive than males, which is consistent with a recent report (White et al, 2023).…”

“…administration in mice reaches its peak within the first 5 min (Jamal et al, 2016; Smolen & Smolen, 1989). Moreover, we had previously determined the dose–response of EtOH in C57BL/6J males in this assay and detected a highly significant antinociceptive effect at the 5‐min timepoint (Okhuarobo, Kreifeldt, et al, 2020).…”

“…On testing days, the mouse was gently introduced into the restrainer, and the distal portion of the tail was positioned under the conical tip of the apparatus. The foot switch was then depressed to apply uniformly increasing pressure onto the tail until the first detected a highly significant antinociceptive effect at the 5-min timepoint (Okhuarobo, Kreifeldt, et al, 2020).…”