KCa2 channels: Novel therapeutic targets for treating alcohol withdrawal and escalation of alcohol consumption

Small-conductance, calcium-activated potassium (KCa2) channels influence neuronal firing properties, intrinsic excitability, and NMDA receptor-dependent synaptic responses and plasticity. In this mini-review, we discuss new evidence that chronic alcohol-associated plasticity critically involves KCa2 channels in hippocampus, ventral tegmental area, and nucleus accumbens. KCa2 channel activity can modulate the magnitude of excitation of midbrain dopamine neurons induced by acute alcohol exposure. Emerging evidence indicates that KCa2 channels regulate neuroadaptations to chronic alcohol that contribute to withdrawal hyperexcitability and escalation of voluntary alcohol consumption. Restoring KCa2 channel activity can attenuate the severity of the alcohol withdrawal syndrome in vivo and withdrawal-associated neurotoxicity in vitro. Pharmacological modulation of KCa2 channels can bi-directionally influence drinking behavior in rat and mouse models of voluntary alcohol consumption. Collectively, these studies using various rodent models have clearly indicated a central role for KCa2 channels in the neuroplasticity of chronic alcohol exposure. In addition, accumulating evidence suggests that KCa2 channels are a novel therapeutic target to alleviate the symptoms of alcohol withdrawal and reduce high amounts of alcohol drinking.