Pharmacological Inhibition of HDAC6 Transiently Reduces Voluntary Ethanol Consumption in Male Mice

Histone deacetylase 6 (HDAC6) inhibition can alleviate depression- and anxiety-like behaviors. Accordingly, HDAC6 may be a promising target to mitigate negative reinforcement in alcohol use disorder (AUD). We previously reported reduced α-tubulin acetylation in mice withdrawn from chronic intermittent ethanol (CIE) vapor inhalation, suggesting potential HDAC6 hyperactivity in this mouse model of AUD. The present study aimed to probe the behavioral significance of this acetylation deficit by testing whether HDAC6 inhibition can reverse ethanol drinking escalation in CIE-exposed mice.

Male C57BL/6J mice were subjected to limited-access ethanol drinking sessions (two-bottle choice, 2BC) combined with CIE to escalate voluntary ethanol intake relative to air-exposed counterparts (Air). Ethanol and saccharin intake during 2BC was measured after acute and subchronic administration of bavarostat, a brain-penetrant HDAC6 inhibitor. Acetyl-lysine and acetyl-α-tubulin levels were quantified via immunoblotting.

Acute administration of bavarostat at 100 mg/kg, but not lower doses, significantly reduced ethanol intake in both Air and CIE mice. Ethanol intake during subchronic administration of 100 mg/kg bavarostat was reduced on the first day in both Air and CIE mice compared to vehicle-treated counterparts, but this effect was lost on subsequent days. CIE mice also consumed more saccharin than Air controls. Bavarostat did not impact saccharin intake in either group. When saccharin was offered along with ethanol, CIE mice consumed significantly more ethanol and less saccharin than Air counterparts, indicating intact taste discrimination. Bavarostat administered prior to brain collection significantly increased acetyl-lysine and acetyl-α-tubulin levels in the frontal cortex, confirming reduced HDAC6 activity. These levels did not differ between Air and CIE mice.

Systemic administration of bavarostat reduces voluntary ethanol drinking in mice. This effect is dose-dependent, selective for ethanol, independent of ethanol dependence, and transient. These findings support HDAC6 as a viable target to acutely reduce the drive to consume ethanol.