Bowles Center for Alcohol Studies, Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599
Department of Anatomy & Neurobiology, and Program in Neuroscience, University of Maryland School of Medicine, Baltimore, Maryland 21201.
J Neurosci. 2023 Jul 12;43(28):5158-5171. doi: 10.1523/JNEUROSCI.0406-22.2023. Epub 2023 May 22.
Alcohol use disorder is complex and multifaceted, involving the coordination of multiple signaling systems across numerous brain regions. Previous work has indicated that both the insular cortex and dynorphin (DYN)/kappa opioid receptor (KOR) systems contribute to excessive alcohol use. More recently, we identified a microcircuit in the medial aspect of the insular cortex that signals through DYN/KOR. Here, we explored the role of insula DYN/KOR circuit components on alcohol intake in a long-term intermittent access (IA) procedure. Using a combination of conditional knock-out strategies and site-directed pharmacology, we discovered distinct and sex-specific roles for insula DYN and KOR in alcohol drinking and related behavior. Our findings show that insula DYN deletion blocked escalated consumption and decreased the overall intake of and preference for alcohol in male and female mice. This effect was specific to alcohol in male mice, as DYN deletion did not impact sucrose intake. Further, insula KOR antagonism reduced alcohol intake and preference during the early phase of IA in male mice only. Alcohol consumption was not affected by insula KOR knockout in either sex. In addition, we found that long-term IA decreased the intrinsic excitability of DYN and deep layer pyramidal neurons (DLPNs) in the insula of male mice. Excitatory synaptic transmission was also impacted by IA, as it drove an increase in excitatory synaptic drive in both DYN neurons and DLPNs. Combined, our findings suggest there is a dynamic interplay between excessive alcohol consumption and insula DYN/KOR microcircuitry. The insular cortex is a complex region that serves as an integratory hub for sensory inputs. In our previous work, we identified a microcircuit in the insula that signals through the kappa opioid receptor (KOR) and its endogenous ligand dynorphin (DYN). Both the insula and DYN/KOR systems have been implicated in excessive alcohol use and alcohol use disorder (AUD). Here, we use converging approaches to determine how insula DYN/KOR microcircuit components contribute to escalated alcohol consumption. Our findings show that insula DYN/KOR systems regulate distinct phases of alcohol consumption in a sex-specific manner, which may contribute to the progression to AUD.
酒精使用障碍是复杂和多方面的，涉及到多个大脑区域的多个信号系统的协调。以前的工作表明，脑岛和内啡肽（DYN）/κ 阿片受体（KOR）系统都与过度饮酒有关。最近，我们在脑岛的内侧部分发现了一个通过 DYN/KOR 信号传递的微电路。在这里，我们在长期间歇接触（IA）程序中探索了脑岛 DYN/KOR 电路成分对酒精摄入的作用。我们使用条件敲除策略和靶向药理学的组合，发现脑岛 DYN 和 KOR 在酒精饮用和相关行为中有不同的、性别特异性的作用。我们的研究结果表明，脑岛 DYN 的缺失阻止了消费的增加，并减少了雄性和雌性小鼠对酒精的总体摄入和偏好。这种效应在雄性小鼠中是特异性的，因为 DYN 的缺失不影响蔗糖的摄入。此外，脑岛 KOR 拮抗作用仅减少了雄性小鼠 IA 早期阶段的酒精摄入和偏好。在任何性别中，脑岛 KOR 缺失都不会影响酒精的摄入。此外，我们发现，长期 IA 降低了雄性小鼠脑岛中 DYN 和深层锥体神经元（DLPN）的内在兴奋性。IA 还影响兴奋性突触传递，因为它增加了 DYN 神经元和 DLPN 中的兴奋性突触驱动。综合起来，我们的研究结果表明，过度饮酒和脑岛 DYN/KOR 微电路之间存在动态相互作用。脑岛是一个复杂的区域，是感觉输入的整合中枢。在我们之前的工作中，我们在脑岛中发现了一个通过κ阿片受体（KOR）和其内源性配体内啡肽（DYN）信号传递的微电路。脑岛和 DYN/KOR 系统都与过度饮酒和酒精使用障碍（AUD）有关。在这里，我们使用多种方法来确定脑岛 DYN/KOR 微电路成分如何促进酒精摄入量的增加。我们的研究结果表明，脑岛 DYN/KOR 系统以性别特异性的方式调节酒精摄入的不同阶段，这可能有助于 AUD 的发展。
