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.
Highlights
One of the well-established molecular targets of ethanol is the large conductance calcium-activated (BK) potassium channel
Deletion of the BK β1 or β4 subunits again did not affect ethanol drinking under these conditions, as indicated by a One-Way analysis of variance (ANOVA) (BK β1: F(1, 39) = 1.66, n.s.; BK β4: F(1, 35) = 0.66, n.s.)
BK β1 DELETION ACCELERATES THE ESCALATION OF ETHANOL DRINKING IN DEPENDENT MICE Repeated exposure to cycles of forced ethanol intoxication and withdrawal through the chronic intermittent ethanol (CIE) procedure gradually increased voluntary ethanol drinking in BK β1 WT mice, while air-exposed counterparts maintained a stable intake throughout the experiment (Figure 2A, PVn weeks)
Summary
One of the well-established molecular targets of ethanol is the large conductance calcium-activated (BK) potassium channel. BK channels are widely distributed throughout the body but abundant in the brain, with high levels of expression in the cortex, limbic system, basal ganglia, thalamus and cerebellum (Chang et al, 1997; Sausbier et al, 2006). They play a key role in several aspects of neuronal physiology, including neurotransmitter release, action potential repolarization, firing patterns, and dendritic excitability [see Faber and Sah (2003) for review]. In D. melanogaster, similar manipulations pointed to a role of BK α subunit in rapid tolerance to the sedative effect of ethanol (Cowmeadow et al, 2005, 2006)
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