2. Academic Validation
  3. Inhibition of HCN channels decreases motivation for alcohol and deprivation-induced drinking in alcohol preferring rats

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

  • Neuropharmacology. 2025 Jun 1:270:110371. doi: 10.1016/j.neuropharm.2025.110371.
Shivani P Vaidya 1,  Roberta G Anversa 1,  Paulo Pinares-Garcia 1,  Leigh C Walker 1,  Natasha Pracejus 1,  Christopher A Reid 1,  Andrew J Lawrence 2
Affiliations

Affiliations

  • 1 The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Australia; The Florey Department of Neuroscience and Mental Health, University of Melbourne, Parkville, Australia.
  • 2 The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Australia; The Florey Department of Neuroscience and Mental Health, University of Melbourne, Parkville, Australia. Electronic address: andrew.lawrence@florey.edu.au.
PMID: 39983913 DOI: 10.1016/j.neuropharm.2025.110371
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.

Keywords

Alcohol; HCN channels; Medial habenula; Motivation.

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