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

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

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引用次数: 0

Abstract

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.

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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).