Prefrontal Cortex K_Ca2 Channels Regulate mGlu₅-Dependent Plasticity and Extinction of Alcohol-Seeking Behavior

Abstract

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.

Mechanisms underlying prelimbic prefrontal cortex mGlu3/mGlu5-dependent plasticity and reversal learning deficits following acute stress

“…Following restraint stress, this M 1 /mGlu 5 -dependent LTD remained intact (Figure 2d). Finally, we assessed the ability of mGlu 5 activation to inhibit the function of SK channels (Cannady et al, 2017). We evaluated SK channel function by measuring Q AHP and found no basal difference following restraint stress (Figure 2e).…”

Cross-species epigenetic regulation of nucleus accumbens KCNN3 transcript variants by excessive ethanol drinking and dependence

“…In the current study, we identified a DMR that maps to an ion channel gene previously implicated in excessive drinking, ethanol-seeking behaviors, and ethanol-induced plasticity of intrinsic excitability (6,10,11,13,17). Our analysis identified a DMR that spans exon 1 and part of intron 1 of monkey and mouse KCNN3 in a region containing CpGs that are highly conserved across species.…”

“…Next, 1.25 μl of cDNA was pre-amplified using 1 μl of PreAmp master mix, 0.5 μl of pooled primers (at 500 nM) and 2.25 μl of RNase-free water. The Pre-Amplification conditions were 95 C for 2 min, followed by 10 cycles at 95 C for 15 s and 60 C for 10 μl Exonuclease I (20 Units/ml) and 1.4 μl of RNase-free water. The reactions were incubated at 37 C for 30 min followed by 80 C for 15 min.…”

“…Small-conductance Ca 2+ -activated K + (KCa2 or SK) channels have emerged from preclinical pharmacogenetic studies as a target for treating AUD (6,(10)(11)(12)(13)(14). KCa2.3 channels are encoded by the KCNN3 gene and are enriched in nucleus accumbens core (NAcC) medium spiny neurons (MSNs) and substantia nigra dopamine neurons where they control neuronal firing patterns (15).…”

Sex differences in the behavioral and synaptic consequences of a single exposure to cannabinoid at puberty and adulthood

“…Considering that the extensive repertoire of synaptic plasticity expressed by medial PFC synapses is sensitive to various regimen of exposure to drugs of abuse (Kassanetz et al 2010; Cannady et al, 2017, Renard et al, 2016; Lovelace et al, 2015; van Huijstee and Mansvelder, 2014) we assessed a second type of plasticity in the PFC which is frequently related to endophenotypes of neuropsychiatric disorders (Labouesse et al 2016; Manduca et al, 2017; Neuhofer et al, 2015; Iafrati et al, 2016; Thomazeau et al, 2014), the NMDAR-dependent LTP (NMDAR-LTP). NMDAR-LTP was ablated in adult male rats while pubescent males were spared.…”