Central Thyroid Hormone Receptor-Beta Agonist Selectively Inhibits Voluntary Alcohol Consumption in Mice

Decades of prior work have indicated associations between thyroid hormone axis dysregulation and alcohol use disorder (AUD). Specifically, disruptions in thyroid hormone levels are related to altered mood, compulsion, craving, and relapse in patients with AUD. Likewise, modulating thyroid hormones in preclinical models can impact ethanol (EtOH) consumption. Recently, we have shown that daily treatment with central nervous system selective thyroid hormone receptor-beta agonist, Sob-AM2, can reduce daily EtOH consumption and preference in male and female C57BL6/J mice at a 1.0 mg/kg dose. However, it is unclear if lower doses can attain reductions in drinking and if the effects of Sob-AM2 habituate with chronic dosing over time. Furthermore, as thyroid hormone signaling within the brain can influence many behaviors, the precise mechanisms driving Sob-AM2's influence on EtOH drinking remain unclear.

In the present study, we tested if treatment with a lower dose of Sob-AM2, 0.3 mg/kg, for 9 days would be sufficient to reduce EtOH intake and preference and if these effects would be sustained over a two-week period. In addition, we tested whether the effects of Sob-AM2 are exerted via altering ETOH elimination from blood, influencing caloric consumption, affecting taste for sucrose, or altering avoidance of a bitter tastant.

We found that Sob-AM2 treatment for 9 days was sufficient to reduce both EtOH intake and preference while increasing water and total fluid intake, and these effects were also present at 23 days of treatment. Meanwhile, treatment with Sob-AM2 did not result in alterations of EtOH elimination rate, nor did it affect food consumption, sucrose consumption, or quinine avoidance in a way that explains reductions in EtOH consumption.

These results demonstrate that agonism of central thyroid hormone receptor-beta selectively decreases voluntary EtOH consumption and may indicate a promising novel therapeutic approach for the treatment of AUD.