اثرات دو طرفه هیپوتیروئیدی و هیپرتیروئیدی در رفتارهای اضطراب و افسردگی مانند در موش

Thyroid hormone disorders have long been linked to depression, but the causal relationship between them remains controversial. To address this question, we established rat models of hypothyroidism using 131iodine (131I) and hyperthyroidism using levothyroxine (LT4). Serum free thyroxine (FT4) and triiodothyronine (FT3) significantly decreased in the hypothyroid of rats with single injections of 131I (5 mCi/kg). These rats exhibited decreased depression-like behaviors in forced swimming test and sucrose preference tests, as well as decreased anxiety-like behaviors in an elevated plus maze. Diminished levels of brain serotonin (5-HT) and increased levels of hippocampal brain-derived neurotrophic factor (BDNF) were found in the hypothyroid rats compared to the control saline–vehicle administered rats. LT4 treatment reversed the decrease in thyroid hormones and depression-like behaviors. In contrast, hyperthyroidism induced by weekly injections of LT4 (15 μg/kg) caused a greater than 10-fold increase in serum FT4 and FT3 levels. The hyperthyroid rats exhibited higher anxiety- and depression-like behaviors, higher brain 5-HT level, and lower hippocampal BDNF levels than the controls. Treatment with the antidepressant imipramine (15 mg/kg) diminished serum FT4 levels as well as anxiety- and depression-like behaviors in the hyperthyroid rats but led to a further increase in brain 5-HT levels, compared with the controls or the hypothyroid rats. Together, our results suggest that hypothyroidism and hyperthyroidism have bidirectional effects on anxiety- and depression-like behaviors in rats, possibly by modulating hippocampal BDNF levels.

Hyperthyroidism and hypothyroidism are the most common disorders affecting the hypothalamic–pituitary–thyroid (HPT) axis. The former is characterized by abnormally high levels of thyroid hormone (TH), like free triiodothyronine (FT3) and free thyroxine (FT4), whereas the latter is characterized by decreased TH levels. A number of clinical studies have suggested that hypothyroidism and hyperthyroidism may lead to comorbid anxiety and depression (Carvalho, 2004, Duntas and Maillis, 2013, Hage and Sami, 2012 and Kamble et al., 2013). Concurrently, it has also been suggested that anxiety and depression may lead to thyroid abnormalities, due to the role of the central serotonin (5-HT) system in HPT axis function (Berent et al., 2014 and Tsuru et al., 2013). However, the precise relationship between hypothyroidism and depression remains unclear (Engum et al., 2002 and Jackson, 1998). Some studies in rats have shown that hypothyroid rats display increased anxiety- and depression-like behaviors (Kulikov et al., 1997 and Montero-Pedrazuela et al., 2006). Consistent with these reports, treatment with T3, T4 or a thyrotropin-releasing hormone analogue achieved antidepressant effects in euthyroid mice and rats (Lifschytz et al., 2006, Lifschytz et al., 2011 and Paulson et al., 2003). Furthermore, a clinical study found that TH and particularly T3 can be used as adjunct therapy to antidepressant treatment for acceleration and potentiation of clinical responses in non-responders (Goodwin et al., 1982). However, this effect was not replicated in another human study (Chang et al., 2013) nor in rats (Lifschytz et al., 2006). In contrast, hyperthyroid rats have been found to exhibit increased depression-like behaviors, whereas no significant effects were observed in hypothyroid rats (Redei et al., 2001). Together, these findings suggest a complex association between TH and anxiety/depression in humans and animals. The etiology of depression remains poorly understood, as do the precise mechanisms underlying the action of antidepressants. Some evidence suggests that abnormal levels of central 5-HT or hippocampal brain-derived neurotrophic factor (BDNF) may play a critical role (Homberg et al., 2014) in depression. In addition, the effect of monoamine-based antidepressants including imipramine has been shown to be dependent on BDNF signaling (Ceretta et al., 2012 and Reus et al., 2013). Depression is a highly heterogeneous disorder with diverse pathogenic origins, one of which may be due to abnormal TH levels that affect 5-HT or BDNF levels. This hypothesis is supported by several reports that demonstrate a close association between TH and 5-HT (Bauer et al., 2002). For example, hypothyroid rats were found to have decreased 5-HT brain levels (Ito et al., 1977, Jacoby et al., 1975 and Tousson et al., 2012), whereas acute or repeated T3 and T4 treatments led to increased 5-HT expression in euthyroid rats (Heal and Smith, 1988 and Sandrini et al., 1996). Furthermore, increased BDNF mRNA and peptide levels were observed in the cortex and hippocampus of hypothyroid rats induced by propylthiouracil (PTU) (Cortes et al., 2012). However, a previous report showed that chronic T3 treatment or hypothyroidism had no effect on hippocampal BDNF mRNA levels (Vaidya et al., 2001). In this study, we investigate the causal relationship between TH and depression and anxiety. To address this question, we used 131iodine (131I) (Harbert, 1987) and levothyroxine (LT4) to establish hypothyroid and hyperthyroid rat models, respectively. We found that 5 mCi/kg 131I and 15 μg/kg LT4 treatments could reliably mimic the symptoms of hypothyroidism and hyperthyroidism, respectively, in human patients, particularly in respect to serum levels of free T4 (FT4) and free T3 (FT3), which are more clinically useful diagnosis indexes for thyroid axis dysfunction than total T4 and total T3 (Bartalena et al., 1996 and Ginsberg, 2003). We assessed the body weight and water and food intake of experimental rats and then performed a number of behavioral tests such as the open field and treadmill tests to evaluate locomotor activity, the elevated-plus maze (EPM) test to assay anxiety-like behaviors, and the forced swimming test (FST) and sucrose preference test to measure depression susceptibility. In addition, we evaluated brain 5-HT and hippocampal BDNF expression levels in both hypothyroid and hyperthyroid groups. The interactions between the serum levels of the thyroid hormones and depression-like behaviors, 5-HT, BDNF were analyzed.

To characterize the hypothyroid rat model, we measured serum FT4 and FT3 concentrations (Dhawan et al., 2007 and Torlak et al., 2007) and found that FT4 and FT3 significantly decreased 10 days after 131I injection (2.5 or 5 mCi/kg, I.G.) compared to the control group using a t test (FT4: 2.5 mCi/kg, P < 0.001, Cohen's d = 0.62; 5 mCi/kg, P < 0.001, Cohen's d = 0.82; FT3: 2.5 mCi/kg, P = 0.006, Cohen's d = 0.54; 5 mCi/kg, P < 0.001, Cohen's d = 0.80; n = 4 in each group; Table 1). We used a dosage of 5 mCi/kg of 131I for the following experiments because it caused a reliable reduction in TH levels that was similar to those in humans with hypothyroid disorder (Lin et al., 2014). We next tested the development of hypothyroidism following a single injection of 131I and found that serum levels of FT4 and FT3 began to decrease significantly on day 5 with a t test (vehicle vs. 131I: FT4: 33.66 ± 2.63 vs. 18.95 ± 3.35 pmol/l, t = 2.434, P = 0.027; FT3: 9.77 ± 0.59 vs. 5.31 ± 0.55 pmol/l, t = 2.005, P = 0.042; n = 3 in each group; Fig. 1A), after which they consistently remained low until at least day 55.