Prefrontal Cortex K2 Channels Regulate mGlu-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 receptors in the infralimbic prefrontal cortex (IL-PFC) facilitates learning during extinction of cue-conditioned alcohol-seeking behavior. Small-conductance calcium-activated potassium (K2) channels have also been implicated in extinction learning of fear memories, and mGlu receptor activation can reduce K2 channel function. Using a combination of electrophysiological, pharmacological, and behavioral approaches, this study examined K2 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-dependent enhancement of extinction learning. Using whole-cell patch-clamp electrophysiology, activation of mGlu in slices significantly reduced K2 channel currents in layer V IL-PFC pyramidal neurons, confirming functional downregulation of K2 channel activity by mGlu receptors. Additionally, positive modulation of K2 channels prevented mGlu receptor-dependent facilitation of long-term potentiation in the IL-PFC. Systemic and intra-IL-PFC treatment with apamin (K2 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 K2 channels significantly attenuated mGlu-dependent facilitation of alcohol cue-conditioned extinction learning. These data suggest that mGlu-dependent facilitation of extinction learning and synaptic plasticity in the IL-PFC involves functional inhibition of K2 channels. Moreover, these findings demonstrate that K2 channels are a novel target to facilitate long-lasting extinction of alcohol-seeking behavior. Alcohol use disorder is a chronic relapsing disorder that is associated with compulsive alcohol-seeking behavior. One of the main causes of alcohol relapse is the craving caused by environmental cues that are associated with alcohol. These cues are formed by normal learning and memory principles, and the understanding of the brain mechanisms that help form these associations can lead to the development of drugs and/or behavior therapies that reduce the impact that these cues have on relapse in alcoholics.