Central thyroid hormone receptor-beta: Sensitivity to alcohol and a role in regulating alcohol drinking

Clinical and preclinical evidence indicate that both peripheral and central elements of the hypothalamic-pituitary-thyroid (HPT) axis are dysregulated in alcohol use disorder, and that thyroid hormone system dysregulation is associated alcohol craving and co-morbid mood and depression-related disorders. Yet, no study has investigated if central nervous system (CNS) thyroid hormone receptors, primary targets of thyroid hormone and major regulators of the HPT axis are involved in alcohol consumption. We utilized a 24-h access two-bottle choice (2BC) voluntary ethanol (EtOH) drinking paradigm to assess if the expression of CNS thyroid hormone receptors is sensitive to voluntary alcohol consumption in C57BL/6 J mice. We found that thyroid hormone receptor-beta (Thrb/THRβ) mRNA expression was significantly reduced in the paraventricular nucleus of the hypothalamus of EtOH drinking mice compared to water controls. In addition, EtOH drinking mice exhibited peripheral elevation of serum triiodothyronine. Next, we utilized the CNS selective THRβ agonist, Sob-AM2, to determine if central activation of THRβ would influence voluntary alcohol drinking in mice in the same EtOH 2BC drinking paradigm. We found that repeated treatment with Sob-AM2 significantly reduced daily EtOH intake and preference, while in conjunction increasing water intake. In summary, we found that hypothalamic Thrb expression is sensitive to voluntary alcohol drinking, and that CNS THRβ activity regulates alcohol consumption in mice. Taken together, our results highlight an important role of central thyroid hormone receptor signalling in alcohol drinking and indicate therapeutic potential of CNS selective thyromimetics in treatment of alcohol use disorder.