NICOTINE MODULATION OF THYROID HORMONE SIGNALING AND ITS CONTRIBUTION TO COGNITION

Abstract

Cigarette smoking is common despite its adverse effects on health, including disruptions to endocrine function. Thyroid hormones may specifically be affected by nicotine exposure through cigarette smoke. The present work begins with a thorough analysis of the literature on thyroid hormones, their contribution to cognition and synaptic plasticity as well as evidence supporting an interaction between nicotine and thyroid signaling. Cigarette smoking/nicotine may disrupt thyroid function in women of reproductive age, heavy smokers, and those prone to thyroid dysfunction due to pre-existing conditions, and these populations would benefit from careful monitoring of their thyroid function. Nicotine also affects cognition and this may drive both the development and maintenance of nicotine addiction. Acute nicotine enhances maladaptive drug-context associations, likely contributing to the development of addiction. The present work evaluates the functional contribution of thyroid receptors (TRs) (ß and α1) to the effect of acute nicotine on hippocampus-dependent memory using a contextual fear conditioning paradigm. It was hypothesized that TRs would be critical for the acute effects of nicotine on contextual fear conditioning. Mice lacking the TRβ and TRα1 gene (KOs) and wildtype littermates (WTs) were administered acute nicotine prior to contextual fear conditioning and results indicated the selective involvement of TRβ in nicotine-enhanced hippocampus-dependent learning. Further examination confirmed select hippocampal TR activation during nicotine enhancement of hippocampus-dependent learning. Withdrawal from chronic nicotine disrupts cognition, leading to continued use and relapse in subjects attempting to quit smoking. Withdrawal from chronic nicotine may induce the development of a hypothyroid condition that could contribute to nicotine withdrawal-related symptoms such as impaired attention and memory. In support, analysis of serum thyroid hormone levels after chronic and withdrawal from chronic nicotine treatment revealed that nicotine withdrawal reduces thyroid hormone levels. Normalizing thyroid hormone levels may therefore represent a novel therapeutic target for ameliorating nicotine withdrawal-associated cognitive deficits. In support of this, supplemental thyroid hormone not only enhanced contextual and cued fear conditioning when administered alone, but also completely abolished nicotine withdrawal-associated deficits in contextual fear conditioning. These results suggest that careful monitoring of thyroid function is warranted, especially in subjects susceptible to the negative effects of nicotine on thyroid hormone levels, and smoking cessation attempts may benefit from successful treatment of thyroid dysfunction.