Cannady Reginald, McGonigal Justin T, Newsom Ryan J, Woodward John J, Mulholland Patrick J, Gass Justin T
Department of Neuroscience.
Department of Psychiatry & Behavioral Sciences, and.
J Neurosci. 2017 Apr 19;37(16):4359-4369. doi: 10.1523/JNEUROSCI.2873-16.2017. Epub 2017 Mar 20.
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.
识别有助于消退学习的新疗法可以增强线索暴露疗法，并降低酗酒者的高复发率。激活边缘下前额叶皮质（IL-PFC）中的代谢型谷氨酸受体（mGlu）有助于在消退线索条件性觅酒行为期间的学习。小电导钙激活钾（K2）通道也与恐惧记忆的消退学习有关，并且mGlu受体激活可以降低K2通道功能。本研究结合电生理学、药理学和行为学方法，将K2通道作为促进大鼠觅酒行为消退的新靶点进行研究。本研究还探讨了IL-PFC内相关的神经元和突触机制，这些机制是mGlu依赖性增强消退学习的基础。使用全细胞膜片钳电生理学方法，在脑片上激活mGlu可显著降低IL-PFC第V层锥体神经元中的K2通道电流，证实mGlu受体对K2通道活性的功能性下调。此外，对K2通道的正向调节可阻止mGlu受体依赖性的IL-PFC长时程增强。用蜂毒明肽（K2通道变构抑制剂）进行全身和IL-PFC内治疗，在多个消退训练中显著增强了觅酒行为的消退，这种效果持续了3周，但在将蜂毒明肽微量注入前额叶前皮质后未观察到。对IL-PFC K2通道的正向调节显著减弱了mGlu依赖性的酒精线索条件性消退学习促进作用。这些数据表明，mGlu依赖性促进IL-PFC中的消退学习和突触可塑性涉及对K2通道的功能性抑制。此外，这些发现表明K2通道是促进觅酒行为长期消退的新靶点。酒精使用障碍是一种慢性复发性疾病，与强迫性觅酒行为有关。酒精复发的主要原因之一是与酒精相关的环境线索引起的渴望。这些线索是由正常的学习和记忆原理形成的，对有助于形成这些关联的脑机制的理解可以导致开发出减少这些线索对酗酒者复发影响的药物和/或行为疗法。
