Identification of a BK channel auxiliary protein controlling molecular and behavioral tolerance to alcohol.

Tolerance, described as the loss of drug effectiveness over time, is an important component of addiction. The degree of acute behavioral tolerance to alcohol exhibited by a naive subject can predict the likelihood of alcohol abuse. Thus, the determinants of acute tolerance are important to understand. Calcium- and voltage-gated (BK) potassium channels, consisting of pore forming α and modulatory β subunits, are targets of ethanol (EtOH) action. Here, we examine the role, at the molecular, cellular, and behavioral levels, of the BK β4 subunit in acute tolerance. Single channel recordings in HEK-293 cells show that, in the absence of β4, EtOH potentiation of activity exhibits acute tolerance, which is blocked by coexpressing the β4 subunit. BK channels in acutely isolated medium spiny neurons from WT mice (in which the β4 subunit is well-represented) exhibit little tolerance. In contrast, neuronal BK channels from β4 knockout (KO) mice do display acute tolerance. Brain slice recordings showed tolerance to EtOH's effects on spike patterning in KO but not in WT mice. In addition, β4 KO mice develop rapid tolerance to EtOH's locomotor effects, whereas WT mice do not. Finally, in a restricted access ethanol self-administration assay, β4 KO mice drink more than their WT counterparts. Taken together, these data indicate that the β4 subunit controls ethanol tolerance at the molecular, cellular, and behavioral levels, and could determine individual differences in alcohol abuse and alcoholism, as well as represent a therapeutic target for alcoholism.