Prefrontal Cortex K_Ca2 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 mGlu₅ receptors in the infralimbic prefrontal cortex (IL-PFC) facilitates learning during extinction of cue-conditioned alcohol-seeking behavior. Small-conductance calcium-activated potassium (K_Ca2) channels have also been implicated in extinction learning of fear memories, and mGlu₅ receptor activation can reduce K_Ca2 channel function. Using a combination of electrophysiological, pharmacological, and behavioral approaches, this study examined K_Ca2 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 mGlu₅-dependent enhancement of extinction learning. Using whole-cell patch-clamp electrophysiology, activation of mGlu₅ in ex vivo slices significantly reduced K_Ca2 channel currents in layer V IL-PFC pyramidal neurons, confirming functional downregulation of K_Ca2 channel activity by mGlu₅ receptors. Additionally, positive modulation of K_Ca2 channels prevented mGlu₅ receptor-dependent facilitation of long-term potentiation in the IL-PFC. Systemic and intra-IL-PFC treatment with apamin (K_Ca2 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_Ca2 channels significantly attenuated mGlu₅-dependent facilitation of alcohol cue-conditioned extinction learning. These data suggest that mGlu₅-dependent facilitation of extinction learning and synaptic plasticity in the IL-PFC involves functional inhibition of K_Ca2 channels. Moreover, these findings demonstrate that K_Ca2 channels are a novel target to facilitate long-lasting extinction of alcohol-seeking behavior.SIGNIFICANCE STATEMENT 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.