BK channel β1 and β4 auxiliary subunits exert opposite influences on escalated ethanol drinking in dependent mice

Abstract

Large conductance calcium-activated potassium (BK) channels play a key role in the control of neuronal activity. Ethanol is a potent activator of BK channel gating, but how this action may impact ethanol drinking still remains poorly understood. Auxiliary β subunits are known to modulate ethanol-induced potentiation of BK currents. In the present study, we investigated whether BK β1 and β4 subunits influence voluntary ethanol consumption using knockout (KO) mice. In a first experiment, mice were first subjected to continuous two-bottle choice (2BC) and were then switched to intermittent 2BC, which progressively increased ethanol intake as previously described in wildtype mice. BK β1 or β4 subunit deficiency did not affect ethanol self-administration under either schedule of access. In a second experiment, mice were first trained to drink ethanol in a limited-access 2BC paradigm. BK β1 or β4 deletion did not affect baseline consumption. Weeks of 2BC were then alternated with weeks of chronic intermittent ethanol (CIE) or air inhalation. As expected, a gradual escalation of ethanol drinking was observed in dependent wildtype mice, while intake remained stable in non-dependent wildtype mice. However, CIE exposure only produced a mild augmentation of ethanol consumption in BK β4 KO mice. Conversely, ethanol drinking increased after fewer CIE cycles in BK β1 KO mice than in wildtype mice. In conclusion, BK β1 or β4 did not influence voluntary ethanol drinking in non-dependent mice, regardless of the pattern of access to ethanol. However, deletion of BK β4 attenuated, while deletion of BK β1 accelerated, the escalation of ethanol drinking during withdrawal from CIE. Our data suggest that BK β1 and β4 subunits have an opposite influence on the negative reinforcing properties of ethanol withdrawal. Modulating the expression, distribution or interactions of BK channel auxiliary subunits may therefore represent a novel avenue for the treatment of alcoholism.

GIRK3 gates activation of the mesolimbic dopaminergic pathway by ethanol

“…It is noteworthy that GIRK3 deletion did not alter ethanol consumption under a continuous schedule of access or in the later part of a 4-h session. This finding points to a selective effect on drinking activity associated with intoxication (as defined by a BAL >80 mg/dL), given that continuous access to ethanol leads to sporadic bouts of drinking and produces only brief peaks of intoxication (29,30), whereas limited access leads to binging and produces BALs that positively correlate with intake in C57BL/6J mice (31)(32)(33). Furthermore, the effect of GIRK3 deletion on binge-like drinking could be reversed by virally mediated expression of GIRK3 in the VTA, and was associated with a blunted response of the mesolimbic DA pathway to ethanol, as demonstrated by ethanolinduced excitation of VTA neurons and DA release in the NAc.…”

Conserved Single Residue in the BK Potassium Channel Required for Activation by Alcohol and Intoxication inC. elegans

“…sensitive and -insensitive components of related ion channels (Mihic et al, 1997;Liu et al, 2003Liu et al, , 2013. While these conventional approaches are powerful and have proved successful, they cannot easily determine whether the mutations identified as important for ethanol effects in vitro are also relevant to ethanolmodulated behaviors in vivo.…”

“…In a chimericbased in vitro approach, the T352 residue would not be targeted, and as a result never identified. Liu et al (2013) demonstrated the importance of the intracellular portion of the BK channel, and Liu et al (2008) found that mutation of calcium-binding residues in the Ca 2ϩ bowl and RCK1 domain abolished the ability of ethanol to activate the BK channel in vitro. However, mutations of the calcium-binding residues also dramatically alter calcium dependence and greatly re- .23).…”

“…The BK channel also mediates ethanol intoxication and/or tolerance in worms, flies, mice, and humans (Davies et al, 2003;Cowmeadow et al, 2005Cowmeadow et al, , 2006Martin et al, 2008;Kreifeldt et al, 2013). Many studies have demonstrated BK channel activity is altered by pharmacologically relevant concentrations (20 -100 mM) of ethanol (Chu and Treistman, 1997;Jakab et al, 1997;Dopico et al, 1998Walters et al, 2000;Brodie et al, 2007).…”

“…For example, phosphorylation of two residues near the first two transmembrane domains switches the action of ethanol from activation to inhibition in the bovine BK channel . Ethanol modulation further depends on the presence of intracellular calcium and specific residues required for calcium activation, as well as the intracellular tail (Liu et al, 2008(Liu et al, , 2013.…”