抑制HCN通道降低酒精偏好大鼠的酒精动机和剥夺性饮酒。

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology Pub Date : 2025-02-19 DOI:10.1016/j.neuropharm.2025.110371

Shivani P. Vaidya , Roberta G. Anversa , Paulo Pinares-Garcia , Leigh C. Walker , Natasha Pracejus , Christopher A. Reid , Andrew J. Lawrence

{"title":"抑制HCN通道降低酒精偏好大鼠的酒精动机和剥夺性饮酒。","authors":"Shivani P. Vaidya , Roberta G. Anversa , Paulo Pinares-Garcia , Leigh C. Walker , Natasha Pracejus , Christopher A. Reid , Andrew J. Lawrence","doi":"10.1016/j.neuropharm.2025.110371","DOIUrl":null,"url":null,"abstract":"<div><div>Globally, around 400 million people live with an alcohol use disorder (AUD), yet current treatments available are suboptimal at a population level. Hyperpolarization-activated cyclic nucleotide-gated cation (HCN) channels are implicated in the modulation of complex motivated behaviours, including reward seeking. Here, we investigated the potential involvement of HCN channels in alcohol reinforcing effects, contributing to alcohol intake and relapse-like drinking following abstinence in iP rats. The functional role of HCN channels in the motivation to acquire alcohol and relapse-like behaviour was tested <em>in vivo</em> through intracerebroventricular (ICV) infusion of a HCN channel inhibitor, ZD7288 prior to operant progressive ratio responding or the alcohol deprivation effect. Acute ICV infusion of ZD7288 (3 μg/5 μL) significantly reduced motivation to acquire alcohol and attenuated the alcohol deprivation effect after 14 days of abstinence, without affecting spontaneous locomotor activity. HCN channels are densely expressed in cholinergic neurons of the medial habenula (mHb), which have been implicated in stress, aversion, and drug/alcohol intake-associated behaviours. To investigate the impact of alcohol on the expression of HCN channels, cholinergic markers and acetylcholine receptors, we performed qPCR on mHb tissue in alcohol-preferring (iP) rats following chronic voluntary alcohol intake or abstinence. qPCR results showed an upregulation of mRNA encoding key ion channels in the mHb following abstinence from chronic voluntary alcohol use. Collectively, these findings suggest that HCN channels contribute to motivation to consume alcohol and relapse-like behaviour during abstinence in iP rats.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"270 ","pages":"Article 110371"},"PeriodicalIF":4.6000,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Inhibition of HCN channels decreases motivation for alcohol and deprivation-induced drinking in alcohol preferring rats\",\"authors\":\"Shivani P. Vaidya , Roberta G. Anversa , Paulo Pinares-Garcia , Leigh C. Walker , Natasha Pracejus , Christopher A. Reid , Andrew J. Lawrence\",\"doi\":\"10.1016/j.neuropharm.2025.110371\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><div>Globally, around 400 million people live with an alcohol use disorder (AUD), yet current treatments available are suboptimal at a population level. Hyperpolarization-activated cyclic nucleotide-gated cation (HCN) channels are implicated in the modulation of complex motivated behaviours, including reward seeking. Here, we investigated the potential involvement of HCN channels in alcohol reinforcing effects, contributing to alcohol intake and relapse-like drinking following abstinence in iP rats. The functional role of HCN channels in the motivation to acquire alcohol and relapse-like behaviour was tested <em>in vivo</em> through intracerebroventricular (ICV) infusion of a HCN channel inhibitor, ZD7288 prior to operant progressive ratio responding or the alcohol deprivation effect. Acute ICV infusion of ZD7288 (3 μg/5 μL) significantly reduced motivation to acquire alcohol and attenuated the alcohol deprivation effect after 14 days of abstinence, without affecting spontaneous locomotor activity. HCN channels are densely expressed in cholinergic neurons of the medial habenula (mHb), which have been implicated in stress, aversion, and drug/alcohol intake-associated behaviours. To investigate the impact of alcohol on the expression of HCN channels, cholinergic markers and acetylcholine receptors, we performed qPCR on mHb tissue in alcohol-preferring (iP) rats following chronic voluntary alcohol intake or abstinence. qPCR results showed an upregulation of mRNA encoding key ion channels in the mHb following abstinence from chronic voluntary alcohol use. Collectively, these findings suggest that HCN channels contribute to motivation to consume alcohol and relapse-like behaviour during abstinence in iP rats.</div></div>\",\"PeriodicalId\":19139,\"journal\":{\"name\":\"Neuropharmacology\",\"volume\":\"270 \",\"pages\":\"Article 110371\"},\"PeriodicalIF\":4.6000,\"publicationDate\":\"2025-02-19\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Neuropharmacology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S0028390825000772\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"NEUROSCIENCES\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Neuropharmacology","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0028390825000772","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"NEUROSCIENCES","Score":null,"Total":0}

引用次数: 0

摘要

在全球范围内，约有4亿人患有酒精使用障碍（AUD），但目前可获得的治疗方法在人口水平上并非最佳。超极化激活的环核苷酸门控阳离子（HCN）通道涉及复杂动机行为的调节，包括寻求奖励。在这里，我们研究了HCN通道在酒精强化作用中的潜在参与，在酒精摄入和戒酒后复发样饮酒中起作用。HCN通道在获得酒精和复发样行为动机中的功能作用，通过在手术前递进比反应或酒精剥夺效应的脑室内（ICV）输注HCN通道抑制剂ZD7288，在体内进行了测试。急性ICV输注ZD7288 （3 μg/5 μL）可显著降低大鼠获得酒精的动机，并在戒酒14天后减弱酒精剥夺效应，但不影响自发性运动活动。HCN通道在内侧束（mHb）的胆碱能神经元中密集表达，这与应激、厌恶和药物/酒精摄入相关行为有关。为了研究酒精对HCN通道、胆碱能标记物和乙酰胆碱受体表达的影响，我们对酒精偏好（iP）大鼠慢性自愿饮酒或戒酒后的mHb组织进行了qPCR。qPCR结果显示，戒除慢性自愿饮酒后，mHb中编码关键离子通道的mRNA上调。总的来说，这些发现表明，HCN通道有助于大鼠戒酒期间饮酒的动机和复发样行为。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

Inhibition of HCN channels decreases motivation for alcohol and deprivation-induced drinking in alcohol preferring rats

查看原文本刊更多论文

Inhibition of HCN channels decreases motivation for alcohol and deprivation-induced drinking in alcohol preferring rats

Globally, around 400 million people live with an alcohol use disorder (AUD), yet current treatments available are suboptimal at a population level. Hyperpolarization-activated cyclic nucleotide-gated cation (HCN) channels are implicated in the modulation of complex motivated behaviours, including reward seeking. Here, we investigated the potential involvement of HCN channels in alcohol reinforcing effects, contributing to alcohol intake and relapse-like drinking following abstinence in iP rats. The functional role of HCN channels in the motivation to acquire alcohol and relapse-like behaviour was tested in vivo through intracerebroventricular (ICV) infusion of a HCN channel inhibitor, ZD7288 prior to operant progressive ratio responding or the alcohol deprivation effect. Acute ICV infusion of ZD7288 (3 μg/5 μL) significantly reduced motivation to acquire alcohol and attenuated the alcohol deprivation effect after 14 days of abstinence, without affecting spontaneous locomotor activity. HCN channels are densely expressed in cholinergic neurons of the medial habenula (mHb), which have been implicated in stress, aversion, and drug/alcohol intake-associated behaviours. To investigate the impact of alcohol on the expression of HCN channels, cholinergic markers and acetylcholine receptors, we performed qPCR on mHb tissue in alcohol-preferring (iP) rats following chronic voluntary alcohol intake or abstinence. qPCR results showed an upregulation of mRNA encoding key ion channels in the mHb following abstinence from chronic voluntary alcohol use. Collectively, these findings suggest that HCN channels contribute to motivation to consume alcohol and relapse-like behaviour during abstinence in iP rats.

求助全文

通过发布文献求助，成功后即可免费获取论文全文。去求助

来源期刊

Neuropharmacology 医学-神经科学

CiteScore

10.00

自引率

4.30%

发文量

288

审稿时长

45 days

期刊介绍： Neuropharmacology publishes high quality, original research and review articles within the discipline of neuroscience, especially articles with a neuropharmacological component. However, papers within any area of neuroscience will be considered. The journal does not usually accept clinical research, although preclinical neuropharmacological studies in humans may be considered. The journal only considers submissions in which the chemical structures and compositions of experimental agents are readily available in the literature or disclosed by the authors in the submitted manuscript. Only in exceptional circumstances will natural products be considered, and then only if the preparation is well defined by scientific means. Neuropharmacology publishes articles of any length (original research and reviews).