The role of anterior insula-brainstem projections and alpha-1 noradrenergic receptors for compulsion-like and alcohol-only drinking
The role of anterior insula-brainstem projections and alpha-1 noradrenergic receptors for compulsion-like and alcohol-only drinking
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DOI：
10.1038/s41386-021-01071-w
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发表时间：
2021-06-24
影响因子：
7.6
通讯作者：
Hopf, Frederic W.
中科院分区：
文献类型：
--
作者：
De Oliveira Sergio, Thatiane;Lei, Kelly;Hopf, Frederic W.
尽管有负面后果，但仍继续消费的类成瘾性饮酒（CLAD）是治疗酒精使用障碍的主要障碍。脑干中的蓝斑区域和前脑皮层区域中的去甲肾上腺素受体（NER）信号传导与压力下的适应性反应有关，这在概念上类似于强迫样反应（尽管存在压力或冲突，但仍有适应性反应）。因此，我们研究了前额叶（aINS）脑干连接和α-1 NERs是否调节强迫性摄入和酒精饮酒（AOD）。盐视紫红质抑制aINS-脑干显著降低CLAD，对仅酒精或糖精摄入没有影响，表明在厌恶性饮酒中特定的aINS-脑干作用。与此相反，哌唑嗪抑制α-1 NERs全身减少CLAD和AOD。与全身性抑制类似，aINS内α-1-NER拮抗作用降低了CLAD和AOD。用GABAR激动剂进行的总体aINS抑制也强烈地降低了CLAD和AOD两者，而不影响糖精摄入或运动，而钙渗透性AMPAR（用NASPM）的aINS抑制降低了CLAD而不影响AOD。最后，哌唑嗪对CLAD和AOD的抑制在全身或aINS内彼此不相关，这表明不同的aINS途径调节CLAD与AOD的可能性，这将需要进一步的研究来明确地解决。总之，我们的研究结果提供了重要的新信息，表明一些aINS通路（aINS脑干和NASPM敏感）专门调节强迫性饮酒，而aINS更普遍地可能包含促进CLAD与AOD的平行通路。这些发现也支持了适应性压力反应系统对多种形式饮酒的重要性。
Compulsion-like alcohol drinking (CLAD), where consumption continues despite negative consequences, is a major obstacle to treating alcohol use disorder. The locus coeruleus area in the brainstem and norepinephrine receptor (NER) signaling in forebrain cortical regions have been implicated in adaptive responding under stress, which is conceptually similar to compulsion-like responding (adaptive responding despite the presence of stress or conflict). Thus, we examined whether anterior insula (aINS)-to-brainstem connections and alpha-1 NERs regulated compulsion-like intake and alcohol-only drinking (AOD). Halorhodopsin inhibition of aINS-brainstem significantly reduced CLAD, with no effect on alcohol-only or saccharin intake, suggesting a specific aINS-brainstem role in aversion-resistant drinking. In contrast, prazosin inhibition of alpha-1 NERs systemically reduced both CLAD and AOD. Similar to systemic inhibition, intra-aINS alpha-1-NER antagonism reduced both CLAD and AOD. Global aINS inhibition with GABAR agonists also strongly reduced both CLAD and AOD, without impacting saccharin intake or locomotion, while aINS inhibition of calcium-permeable AMPARs (with NASPM) reduced CLAD without impacting AOD. Finally, prazosin inhibition of CLAD and AOD was not correlated with each other, systemically or within aINS, suggesting the possibility that different aINS pathways regulate CLAD versus AOD, which will require further study to definitively address. Together, our results provide important new information showing that some aINS pathways (aINS-brainstem and NASPM-sensitive) specifically regulate compulsion-like alcohol consumption, while aINS more generally may contain parallel pathways promoting CLAD versus AOD. These findings also support the importance of the adaptive stress response system for multiple forms of alcohol drinking.