Abstract

The rewarding properties of alcohol (ethanol) play a central role in perpetuating dysfunctional consumption behaviors. Ethanol activates dopaminergic neurons in the ventral tegmental area (VTA), increasing dopamine release in the nucleus accumbens (NAc) and driving its rewarding effects. Previous studies have shown that these responses are modulated by the activity of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, as non-selective HCN inhibitors such as ZD7288 reduce ethanol-induced activation of dopamine neurons. HCN2 overexpression in UChB alcohol-preferring rats increases ethanol intake and dopamine release, while silencing HCN2 reduces ethanol consumption. These findings identify HCN2 channels as a key mediator of ethanol reward, prompting the exploration of HCN2-selective blockers as therapeutic agents. This study investigated the effects of intracerebroventricular administration of the HCN blockers SMU-XYC5 (HCN2-preferring), MEL55A (HCN1/HCN2-preferring), and ZD7288 (non-selective) on ethanol-induced dopamine release, reward-related behaviors, and ?FosB levels in the NAc of UChB alcohol-preferring rats. All blockers significantly reduced ethanol-induced dopamine release in the NAc shell in a dose-dependent manner (p < 0.01), with SMU-XYC5 showing the highest potency. Voluntary ethanol consumption was markedly decreased by ~70 % during treatment, with sustained reductions observed post-treatment for MEL55A and high SMU-XYC5 doses. Noteworthy, all blockers prevented ethanol-induced conditioned place preference (p > 0.05) and reduced (~40 %) ethanol-induced ?FosB levels in the NAc core, without affecting locomotor activity or total fluid intake. These findings suggest HCN2 channels as a key regulator of ethanol reward and support HCN2-preferential blockers as a potential therapeutic option for alcohol use disorders. © 2025 Elsevier Inc.