Ivermectin reduces withdrawal-induced alcohol intake in rats: Association with CeA GABAergic enhancement and P2rx4 genetic liability.

Although FDA-approved medications for alcohol use disorder are available, their efficacy varies across patients, highlighting the need for novel therapeutics that address inter-individual differences in disease etiology and treatment response. Genetic models, particularly heterogeneous stock (HS) rats, recapitulate human-like genetic diversity and behavioral heterogeneity, enabling the dissection of individual differences in vulnerability to AUD and pharmacotherapeutic sensitivity. P2X4 receptors, which are encoded by the gene P2rx4, are ATP-gated ion channels are inhibited by ethanol and abundantly expressed in neurons found in reward and stress circuits. P2X4 receptors have emerged as key modulators of ethanol sensitivity and consumption in preclinical models. Here, we genetically predicted P2rx4 expression in whole brain in 131 male and female HS rats exposed to chronic intermittent ethanol vapor and phenotyped for self-administration during acute abstinence. Rats were dichotomized into genetically predicted high and low expression groups. We found that higher genetically predicted P2rx4 expression was associated with increased post-vapor intake and escalation. In 32 CIE-escalated rats, ivermectin, a positive allosteric modulator of P2X4 receptors, dose-dependently reduced drinking. We stratified rats into three groups: non-responders, mild responders, and high responders. Electrophysiological recordings from CeA slices revealed that ivermectin differentially enhanced GABAergic IPSCs: high-responders exhibited sustained increases in IPSC frequency and selective amplitude reductions, while the two other groups showed transient frequency increases. All groups displayed prolonged rise times, however non-responders showed extended decay times. These findings suggest that P2rx4 upregulation serves as a vulnerability marker for dependence-like behaviors, with ivermectin attenuating withdrawal-driven alcohol consumption by enhancing CeA GABAergic inhibition.