Details

Autor(en) / Beteiligte

• Okhuarobo, Agbonlahor
• Kreifeldt, Max
• Gandhi, Pauravi J.
• Lopez, Catherine
• Martinez, Briana
• Fleck, Kiera
• Bajo, Michal
• Bhattacharyya, Pushpita
• Dopico, Alex M.
• Roberto, Marisa
• Roberts, Amanda J.
• Homanics, Gregg E.
• Contet, Candice

Titel

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

Ist Teil von

• Molecular psychiatry, 2024-02, Vol.29 (2), p.529-542

Ort / Verlag

London: Nature Publishing Group UK

Erscheinungsjahr

2024

Quelle

MEDLINE

Beschreibungen/Notizen

• Large conductance potassium (BK) channels are among the most sensitive molecular targets of ethanol and genetic variations in the channel-forming α subunit have been nominally associated with alcohol use disorders. However, whether the action of ethanol at BK α influences the motivation to drink alcohol remains to be determined. To address this question, we first tested the effect of systemically administered BK channel modulators on voluntary alcohol consumption in C57BL/6J males. Penitrem A (blocker) exerted dose-dependent effects on moderate alcohol intake, while paxilline (blocker) and BMS-204352 (opener) were ineffective. Because pharmacological manipulations are inherently limited by non-specific effects, we then sought to investigate the behavioral relevance of ethanol’s direct interaction with BK α by introducing in the mouse genome a point mutation known to render BK channels insensitive to ethanol while preserving their physiological function. The BK α K361N substitution prevented ethanol from reducing spike threshold in medial habenula neurons. However, it did not alter acute responses to ethanol in vivo, including ataxia, sedation, hypothermia, analgesia, and conditioned place preference. Furthermore, the mutation did not have reproducible effects on alcohol consumption in limited, continuous, or intermittent access home cage two-bottle choice paradigms conducted in both males and females. Notably, in contrast to previous observations made in mice missing BK channel auxiliary β subunits, the BK α K361N substitution had no significant impact on ethanol intake escalation induced by chronic intermittent alcohol vapor inhalation. It also did not affect the metabolic and locomotor consequences of chronic alcohol exposure. Altogether, these data suggest that the direct interaction of ethanol with BK α does not mediate the alcohol-related phenotypes examined here in mice.