Prefrontal Cortex KCa2 Channels Regulate mGlu5-Dependent Plasticity and Extinction of Alcohol-Seeking Behavior

Identifying novel treatments that facilitate extinction learning could enhance cue-exposure therapy and reduce high relapse rates in alcoholics. Activation of mGlu(5) receptors in the infralimbic prefrontal cortex (IL-PFC) facilitates learning during extinction of cue-conditioned alcohol-seeking behavior. Small-conductance calcium-activated potassium (K(Ca)2) channels have also been implicated in extinction learning of fear memories, and mGlu5 receptor activation can reduce K(Ca)2 channel function. Using a combination of electrophysiological, pharmacological, and behavioral approaches, this study examined K(Ca)2 channels as a novel target to facilitate extinction of alcohol-seeking behavior in rats. This study also explored related neuronal and synaptic mechanisms within the IL-PFC that underlie mGlu(5)-dependent enhancement of extinction learning. Using whole-cell patch-clamp electrophysiology, activation of mGlu5 in ex vivo slices significantly reduced K(Ca)2 channel currents in layer V IL-PFC pyramidal neurons, confirming functional downregulation of K(Ca)2 channel activity by mGlu(5) receptors. Additionally, positive modulation of K(Ca)2 channels prevented mGlu(5) receptor-dependent facilitation of long-term potentiation in the IL-PFC. Systemic and intra-IL-PFC treatment with apamin (K(Ca)2 channel allosteric inhibitor) significantly enhanced extinction of alcohol-seeking behavior across multiple extinction sessions, an effect that persisted for 3 weeks, but was not observed after apamin microinfusions into the prelimbic PFC. Positive modulation of IL-PFC K(Ca)2 channels significantly attenuated mGlu(5)- dependent facilitation of alcohol cue-conditioned extinction learning. These data suggest that mGlu(5)-dependent facilitation of extinction learning and synaptic plasticity in the IL-PFC involves functional inhibition of K(Ca)2 channels. Moreover, these findings demonstrate that K(Ca)2 channels are a novel target to facilitate long-lasting extinction of alcohol-seeking behavior.