Recent evidence suggests that ethanol-associated homeostatic plasticity involves compensatory increases in synaptic NMDA receptors that contributes to aberrant hyperexcitability upon cessation of consumption and may underlie craving that leads to the high incidence of relapse in alcohol dependent individuals. Small-conductance calcium-activated potassium (SK) channels regulate NMDA receptor-dependent calcium influx and are critical modulators of hippocampal-dependent synaptic plasticity. This is consistent with the suggestion that SK2 channels and NMDA receptors form a regulatory calcium-mediated feedback loop within individual dendritic spines. Preliminary evidence demonstrates a reduction in surface SK2 channels following chronic ethanol treatment that leads to a disruption of the SK channel-NMDA receptor feedback loop. Moreover, we have demonstrated that modulation of SK channels can influence voluntary drinking behavior. Thus, the overarching hypothesis is that SK2 channels contribute to alcohol-associated plasticity of glutamatergic synapses and that positive modulation of SK channels reduces the severity of withdrawal-related hyperexcitability and decreases alcohol intake. These studies will test the hypotheses that: 1) chronic ethanol exposure produces a homeostatic reduction in SK2 channel expression through PKA signaling, 2) modulation of the SK channel-NMDA receptor feedback loop can reduce ethanol withdrawal , hyperexcitability and neurotoxicity, and 3) modulation of the synaptic feedback loop will reduce voluntary alcohol consumption. Decreases in SK2 channels and increases in NMDA receptors may represent a common homeostatic adaptive response to prolonged reductions in NMDA receptor activity during ethanol exposure. Furthermore, this functional uncoupling of the SK2 channel-NMDA receptor calcium-mediated feedback loop may contribute to tolerance development and to withdrawal hyperexcitability.

Results from this ROO application will provide insight into mechanisms that regulate ethanol withdrawal hyperexcitability and voluntary alcohol consumption. In addition, these studies may identify a novel therapeutic target for the treatment of alcohol dependence.