Review | Published:

Thyroid hormones, serotonin and mood: of synergy and significance in the adult brain

Molecular Psychiatry volume 7, pages 140156 (2002) | Download Citation



The use of thyroid hormones as an effective adjunct treatment for affective disorders has been studied over the past three decades and has been confirmed repeatedly. Interaction of the thyroid and monoamine neurotransmitter systems has been suggested as a potential underlying mechanism of action. While catecholamine and thyroid interrelationships have been reviewed in detail, the serotonin system has been relatively neglected. Thus, the goal of this article is to review the literature on the relationships between thyroid hormones and the brain serotonin (5-HT) system, limited to studies in adult humans and adult animals. In humans, neuroendocrine challenge studies in hypothyroid patients have shown a reduced 5-HT responsiveness that is reversible with thyroid replacement therapy. In adult animals with experimentally-induced hypothyroid states, increased 5-HT turnover in the brainstem is consistently reported while decreased cortical 5-HT concentrations and 5-HT2A receptor density are less frequently observed. In the majority of studies, the effects of thyroid hormone administration in animals with experimentally-induced hypothyroid states include an increase in cortical 5-HT concentrations and a desensitization of autoinhibitory 5-HT1A receptors in the raphe area, resulting in disinhibition of cortical and hippocampal 5-HT release. Furthermore, there is some indication that thyroid hormones may increase cortical 5-HT2 receptor sensitivity. In conclusion, there is robust evidence, particularly from animal studies, that the thyroid economy has a modulating impact on the brain serotonin system. Thus it is postulated that one mechanism, among others, through which exogenous thyroid hormones may exert their modulatory effects in affective illness is via an increase in serotonergic neurotransmission, specifically by reducing the sensitivity of 5-HT1A autoreceptors in the raphe area, and by increasing 5-HT2 receptor sensitivity.


The thyroid system and mood modulation in affective illness

Disorders of the thyroid gland are frequently associated with severe mental disturbances.1,2 This intimate association between the thyroid system and behavior has been the impetus for exploring the effects of thyroid hormones in modulating affective illness, and the role of the hypothalamic-pituitary thyroid (HPT) axis in the pathophysiology of mood disorders.3 Thyroid hormones (TH) have a profound influence on behavior and mood, and appear to be capable of modulating the phenotypic expression of major affective illness.3,4,5,6 Thyroid supplementation is now widely accepted as an effective treatment option for patients with affective disorders.7,8,9

Actions of thyroid hormones in the adult brain

It is well established that thyroid hormones are essential for both the development and maturation of the human brain, affecting such diverse events as neuronal processing and integration, glial cell proliferation, myelination, and the synthesis of key enzymes required for neurotransmitter synthesis.10,11 Thyroid deficiency during the perinatal period results in irreversible brain damage and mental retardation. However, despite this accepted body of knowledge and in disregard of the clinical and therapeutic observations in association with affective illness, the action of thyroid hormones in CNS function in adults has not been widely acknowledged by general endocrinologists. This lack of interest seems to have originated in the 1950s and 1960s, when early physiological studies suggested that oxygen consumption in the mature human brain did not change with changing thyroid status.12,13,14

Thus, in contrast to our understanding of thyroid hormone's critically important role in the development of the CNS, until recently, little has been known about the function and effects of thyroid hormones in the mature mammalian brain.15 However, with improved methods in basic research the action of thyroid hormones in the mature brain has become a subject of greater interest.16 There are several lines of evidence suggesting that thyroid hormones affect mature brain function. First, thyroid hormone receptors are prevalent in the mature brain. Nuclear receptors for T3, the thyroid hormone with the highest biological activity, are widely distributed in adult rat brain with higher densities of nuclear T3 receptors in phylogenetically younger brain regions—in the amygdala and hippocampus—and lower densities in the brain stem and cerebellum.17,18 A second line of evidence pertains to brain thyroid hormone metabolism. The process of 5-deiodination by which both thyroid hormones, T4 and T3, are metabolized to inactive iodothyronines has been demonstrated to be different in the adult brain from that in peripheral tissues. Specifically, the type D2 and type D3 deiodinases catalyze these metabolic processes in spatially distinct patterns in the central nervous system and appear to be segregated into specific cell types.19 D2 is expressed primarily in the brain and anterior pituitary gland where it metabolizes T4 to the active thyroid hormone form, T3. The activity of D2 in distinct regions of the brain varies widely, with the highest levels found in cortical areas and lesser activity in the midbrain, pons, hypothalamus and brainstem.20 In rat brain D2 is expressed in neurons, in particular in the nerve terminals, but also in astrocytes.21 Third, thyroid hormones have been detected in relatively high (nanomolar) concentrations in cortical tissue.22 In contrast to peripheral tissue where T4 concentrations usually far exceed those of T3, in the brain T4 and T3 concentrations are in an equimolar range.

Monoamines and mood

Over the past two decades it has become apparent that the monoamines, specifically norepinephrine and serotonin play a major role in mood modulation.23,24,25,26,27 These long track systems which begin in the brainstem and extend through the midbrain into the limbic system and cortex modulate the activity of many of the brain regions related to emotion and memory. The interdependence of these long tracks—including the dopamine system—with thyroid hormone metabolism has become better understood as our technology has improved.

The catecholaminergic system was initially investigated largely because of the known physiological association between sympathetic activity and thyroid hormones.26 Thyroid hormones appear to play an important role in regulating central noradrenergic (NA) function and it has been suggested that thyroid dysfunction may be linked with abnormalities in central NA neurotransmission.27 Evidence for a thyroid–NA interaction derives largely from immunohistochemical mapping studies demonstrating that T3 is concentrated in both nuclei and projection sites of central NA systems.28 Recent evidence that T3 is also delivered from the locus coeruleus to its NA targets via anterograde axonal transport indicates that T3 may function as a cotransmitter with norepinephrine in the adrenergic nervous system.29

However, the neuropharmacological effects and functional pathways underlying the therapeutic effects of thyroid hormones in patients with affective disorders are still unclear. One of the most intuitive hypotheses postulates the existence of a brain thyroid hormone deficiency in affective illness. Thyroid hormone therapy can then be considered a replacement therapy with a possible mechanism of action being its pharmacological effects on monoamine neurotransmitter systems, eg, by increasing β-adrenergic receptor activity and thus promoting the action of catecholamines at central receptor sites.27

The CNS serotonin system

As with the noradrenergic and dopaminergic systems, the bulk of the CNS serotonergic nerve terminals originate in the neuronal cell bodies of the brainstem raphe nuclei and project, both rostrally and caudally, to neuroanatomically discrete areas throughout the brain but with extensive innervation of the cerebral cortex and the limbic system.30 Although the serotonin system has been given prominence in recent deliberation regarding mood modulation, particularly since the advent of drugs that specifically interfere with serotonin neuronal reuptake systems, there has been little investigation of the relationship of this system to the thyroid system. This paper analyzes the existing literature pertaining to this relationship and explores areas which may be fruitful for further study.

The brain serotonin system and its role in depression

Basic and clinical research of the past three decades has yielded compelling evidence that the serotonergic system is intimately involved in the pathogenesis of depression.23,25,31,32 Changes in serotonergic neurotransmission have been repeatedly associated with the therapeutic response to antidepressant and mood stabilizing medication.23,33 Almost all currently employed treatments for depression, including the tricyclic antidepressants, the SSRIs, the MAO inhibitors, lithium and ECT, directly or indirectly augment serotonergic neurotransmission.34 Another line of evidence derives from the tryptophan-depletion paradigm, a procedure that lowers central serotonin levels, and which produces a rapid relapse of SSRI-responsive depression.33,35 Other support comes from studies demonstrating lowered levels of 5-hydroxyindoleacetic acid (5-HIAA), a metabolite of 5-HT whose levels reflect central serotonin activity, in the CSF in unmedicated depressed patients.25 In brain imaging studies, clinical depression was associated with reduced serotonin transporter availability.36,37

Objectives and elements of this review

This article explores the hypothesis that the mood modulating activity of thyroid hormones may be mediated in part by interaction with the brain serotonin system, specifically by enhancing cortical serotonergic neurotransmission. Because of the specific organization of the brain serotonin system, an analysis of the literature has been divided into anatomical areas: specifically the brainstem, the midbrain, the limbic system, and the cortex; those studies that were not specified in regard to brain area, as were many of the early studies, are referred to as ‘whole brain studies’. The other important element running through these analyses is the technical advance which has occurred over the 25 years that are the subject of our review. Specifically, many early studies were based upon crude analyses of levels of serotonin and its metabolites in homogenized brain tissue of animals that had been previously exposed to hypo- or hyperthyroid states. As technology advanced and our chemical dissection of thyroid hormone system metabolism gained specificity, more sophisticated studies emerged that have improved our understanding of turnover and receptor activity. In the 1990s, ligand studies and studies of transporter systems began to complement the earlier studies, and most recently, microdialysis techniques have provided new insights by measuring levels of serotonin in vivo. We have tried to reflect this technical advance in the analysis of the papers that are reviewed.

Methods of literature research

An attempt was made to identify all reports studying the interaction between thyroid hormones and the brain serotonergic system both in animals and in humans, but with a focus on studies in the adult brain. A computer-aided search of the National Library of Medicine MEDLINE database for 1966 to August 2000 using the subject headings ‘thyroid hormones’, ‘serotonin’, ‘brain’ and ‘affective disorders’ was performed, supplemented by the bibliographies of reports identified.

Results of the review

Effects of experimentally-induced hypothyroid states on brain serotonin system in animals

Historical perspective: studies in neonatal animals

Stimulated by the essential role of thyroid hormones in brain development, the effects of hypothyroidism on serotonergic neurotransmission were originally studied in neonatal rats. In these studies, 5-hydroxytryptamine (5-HT, serotonin) and 5-HIAA, the main 5-HT metabolite, were found to be significantly elevated and the serotonin precursor 5-hydroxytryptophan (5-HTP) to be decreased compared to euthyroid controls indicating an increased serotonin turnover rate in the neonatal period.38 Other data have demonstrated that neonatal hyperthyroidism induced by daily application of T3 also resulted in an increased turnover of 5-HT.39

Measurements of 5-HT and its metabolites in adult hypothyroid animals

In the adult rat brain, hypothyroidism generally induced lesser changes in the serotonergic system compared to the studies in neonatal animals. Thirteen studies were identified that measured the effects of experimentally-induced hypothyroidism on the serotonergic system. The methods and results of these studies are shown in Table 1. One early study measured brainstem 5-HT concentrations and did not find significant differences compared to euthyroid animals.40 Later, using more sensitive assay techniques, five studies measured 5-HT and 5-HIAA concentration or the 5-HIAA/5-HT ratio as an indicator of the serotonin turnover and reported increased 5-HT metabolites in the brainstem41,42,43,44,45 (notice: one study calculated the inverse ratio, 5-HT/5-HIAA41). Reduced 5-HT concentrations in the cortex,46,47 and reduced concentrations of the serotonin precursor 5-HTP were reported in the whole brain48 of hypothyroid adult rats. These findings of increased 5-HT turnover in the brainstem and decreased levels of 5-HT and its precursors in the cortex/whole brain are in accordance with the hypothesis that increased brainstem 5-HT turnover might activate raphe 5-HT1A autoreceptors and subsequently decrease serotonin release in the cortical projection areas.23

Table 1: Effects of experimentally-induced hypothyroid states on brain serotonin system

Receptor studies: changes in 5-HT1A and 5-HT2 receptors in the adult hypothyroid brain

Among the many 5-HT receptor subtypes with different regional distributions throughout the CNS, it is the 5-HT1A and 5-HT2 receptor densities that have been most studied in experimentally-induced hypothyroid animals. The 5-HT1A receptor subtype, predominantly located on the cell bodies and dendrites of the serotonergic neurons in the raphe nuclei, functions as a control point of activity for these neurons. In contrast, the postsynaptic entities of 5-HT neurotransmission consist of several subtypes of 5-HT2 receptors located in distinct projection areas of the 5-HT neurons.

In experimentally-induced hypothyroid states the 5-HT1A (presynaptic) receptor density in the brainstem and midbrain was not altered49,50,51,52 (Table 1). Studies on the density of 5-HT1A (postsynaptic) receptors outside the brainstem yielded contradictory results. An increase in cortical and hippocampal 5-HT1A (postsynaptic) receptors was observed by Tejani-Butt et al50 but not by Hong et al49 and Kulikov et al,51 who found no significant differences compared to euthyroid adult rodents.

An early study by Mason et al52 found a decrease in 5-HT2 receptor density in the striatum but not in the cortex of hypothyroid adult rats. However, when 5-HT2A receptors were assessed selectively in severely hypothyroid rats, a significant cortical reduction was recently reported by Kulikov et al.51

Hence in summary, several lines of evidence indicate that an experimentally-induced hypothyroid state in adult rodents is associated with an increased 5-HT turnover rate in the brainstem, but not with a change in 5-HT1A autoreceptor density in the raphe area. There is also some evidence that hypothyroid states result in a decrease in cortical 5-HT serotonin concentrations and 5-HT2A receptor density.

Effects of thyroid hormone application on brain serotonin system in animals

Fourteen studies were located that measured the acute effects of thyroid hormone (T3 and/or T4) on 5-HT and/or L-tryptophan, 5-hydroxytryptophan (5-HTP), and 5-HIAA concentrations in adult rodent brain (for methods and results see Table 2).

Table 2: Effects of thyroid hormone application on brain serotonin system

Acute effects of thyroid hormones on levels of 5-HT and its metabolites in the brainstem and midbrain

Rastogi and Singhal53 observed an increase in the 5-HT precursor L-tryptophan (L-TP), and Heal and Smith54 found an increase in both 5-HT and 5-HIAA in the midbrain after T3 application in euthyroid animals. In contrast, Henley et al42,45 examined animals after thyroidectomy, which resulted in an elevated serotonin turnover rate; in these animals, T3 replacement resulted in a significant decrease in the 5-HIAA/5-HT ratio in the brainstem. In the two studies of thyroid replacement after thyroidectomy, T3 replacement for longer than 3.5 days reduced the 5-HT turnover in caudal brainstem to completely normal values. The activity of tryptophan hydroxylase (TPH), the rate-limiting enzyme in the synthesis of 5-HT, was found unaltered in the midbrain after T3 application.51,53

Acute effects of thyroid hormones on levels of 5-HT and its metabolites in cortex and whole brain

More consistent than the effects of ‘micro-dissection’ reported above were the results of studies that measured the effects of thyroid hormone on levels of 5-HT and its metabolites in the cortex or in the whole brain. Thyroid hormone application to euthyroid rodents increased cortical or whole brain 5-HT, 5-HTP and 5-HIAA concentrations in 10 studies.41,46,47,48,54,55,56,57,58,59 These results indicating increased cortical 5-HT turnover were consistent despite changing technologies over a 25-year period, and may be considered robust. In only one study did the whole brain 5-HT level not increase after thyroid hormone administration.60

Chronic effects of thyroid hormones on levels of 5-HT and its metabolites in cortex and whole brain

Fewer studies assessed the effects of a single vs multiple T3 or T4 application on cortical serotonergic neurotransmission in euthyroid rodents54,55,58,59 (Table 2). In three of four studies, increases in cortical or whole brain 5-HT, 5-HTP and 5-HIAA contents were observed only after repeated (chronic) thyroid hormone application.54,55,59

Thus, the increased concentration of 5-HT and its precursors and metabolites in the cortex or whole brain that were observed in the majority of studies were more pronounced after repeated (chronic) thyroid hormone application. Similar studies investigating the effects on 5-HT levels in the brainstem and midbrain are less consistent (Table 2).

Effects of thyroid hormones on 5-HT1A receptor density and sensitivity

Three autoradiographic studies have reported that thyroid hormone application induces no significant reduction in raphe and midbrain 5-HT1A receptor density.49,50,51 However, a recent study by Gur et al59 indicated a loss of autoinhibitory 5-HT1A receptor sensitivity mediated by T3 (Table 2). Gur et al,59 for the first time in the study of the 5-HT-thyroid interaction, used an in vivo microdialysis technique that allows the measurement of 5-HT concentrations in the brain with a high degree of accuracy in the living animal. In this study, the decrease in hippocampal and cortical serotonin release that follows the application of a 5-HT1A agonist via the activation of inhibitory autoreceptors was significantly reduced by T3 alone, or T3 combined with clomipramine administration in euthyroid rats.59

Effects of thyroid hormones on 5-HT2 receptor density and sensitivity

The database concerning changes in 5-HT2 receptor density after thyroid hormone application reveals contradictions. Mason et al52 observed an increase in 5-HT2 receptor density in the striatum, hippocampus and cortex of thyroidectomized rats only after long-term application of a relatively high dose of either T3 (250–1000 μg kg−1 for 7–10 days) or T4 (250–500 μg kg−1 for 7–10 days). Kulikov et al51 showed that T4 application in thyroidectomized animals returned cortical 5-HT2A receptor densities to normal levels, irrespective of whether a replacement or high T4 dose was applied (15 μg kg−1 vs 200 μg kg−1 T4 for 21 days each). Lower doses and shorter duration of T3 application yielded different results: Sandrini et al58 found no significant effect on 5-HT2 receptor density in the hippocampus and a decrease in cortical 5-HT2 receptor density after application of T3 in euthyroid rats (100 μg kg−1 for 3–7 days). In the study of Heal and Smith54 the same T3 dose applied to euthyroid rats (100 μg kg−1 for 10 days) also decreased cortical 5-HT2 receptor density. A reduction in prefrontal 5-HT2A receptors was observed after coadministration of T3 and the antidepressant desipramine.61

A thyroid hormone-induced change in receptor sensitivity was observed for cortical 5-HT2 receptor function in adult euthyroid rats. Heal and Smith54 observed an increase in 5-HT2 receptor sensitivity after short-term T3 application, and Atterwill60 reported similar findings after both short- and long-term T3 application (Table 2). Under stress conditions, on the other hand, administration of high doses of T4 (350 μg kg−1 for 7 days) resulted in a blunting of the immobilization stress-induced activation of hypothalamic 5-HT2 receptors.62

Effects of low vs high doses of thyroid hormones on the 5-HT system

Some studies compared the effects of a low (replacement) vs a high dose of thyroid hormone on 5-HT receptors.50,51,52 The effects on the serotonergic system were more pronounced with higher doses of thyroid hormone in two out of three studies.50,52 Cortical and hippocampal 5-HT2 receptors.52 and hippocampal and hypothalamic (postsynaptic) 5-HT1A receptor density50 were significantly increased after administration of higher doses of T3 or T4. However, excess serum thyroid hormone in thyroidectomized rats, achieved by administration of high doses of T4, did not produce any changes in cortical 5-HT2A receptors when compared to thyroidectomized animals with normalized thyroid hormone levels.51

In summary, 5-HT receptor studies in adult euthyroid rodents indicate that thyroid hormone application may desensitize presynaptic 5-HT1A raphe autoreceptors, and thus increase cortical serotonin release, an effect similar to that described after addition of the 5-HT1A receptor antagonist pindolol to an ongoing SSRI treatment.63 The receptor studies also indicate that thyroid hormone application may increase cortical 5-HT2 receptor sensitivity. This increase in 5-HT2 receptor function does not seem to be linear, as stress-induced activation of hypothalamic 5-HT2 receptors was blunted in hyperthyroid rats.62 Cortical 5-HT2 receptor densities were only increased after prolonged treatment with relatively high doses of thyroid hormone in thyroidectomized rats. In contrast, standard doses of T3 in euthyroid rats resulted in a decrease in the number of cortical 5-HT2 receptors.

Clinical studies of the thyroid–serotonin interaction

The serotonin system in hypothyroid patients and effects of thyroid hormone replacement

In three studies, parameters of the serotonergic system were examined in hypothyroid patients (Table 3). Sjöberg et al64 measured 5-HT, L-TP and 5-HIAA concentrations in the CSF of seven hypothyroid patients before and after T4 replacement. A significant decrease in the serotonin precursor L-TP after T4 treatment was found which may indicate increased conversion to 5-HT. However, no significant increase in CSF 5-HT or 5-HIAA concentrations after T4 replacement was found.

Table 3: Clinical studies in humans on the thyroid–serotonin interaction

Several studies in an effort to evaluate functional components of the serotonergic system in humans have examined the neuroendocrine responses to d-fenfluramine (D-FEN). D-fenfluramine stimulates the serotonergic projecting pathways from the dorsal raphe nuclei to the paraventricular nucleus of the central hypothalamus and seems to release cortisol via activation of 5-HT1A or 5-HT2 receptors.65,66 Two such challenge studies found a significantly decreased D-FEN-induced cortisol response in hypothyroid patients65,67 (Table 3), which normalized with T4 replacement.67 This enhancement of central 5-HT2 receptor activity after T4 application in previously hypothyroid patients67 is in agreement with the findings in animal studies of increased 5-HT2 receptor sensitivity after T3 application.54,60

The serotonin system in hyperthyroid patients

One study examined peripheral 5-HT concentrations and the activity of the metabolizing enzyme monoamine oxidase (MAO) before and after treatment in 45 hyperthyroid patients and compared the activity to that present in healthy, euthyroid controls. Serotonin blood levels were found to be increased, and MAO activity decreased, in the hyperthyroid state68 (Table 3). After 3 months of treatment with carbimazole and the associated decline of plasma T3 and T4 concentrations towards normal levels, MAO activity increased and plasma serotonin concentrations decreased, however, not to within the range of the normal control subjects.68 These findings suggest altered serotonin metabolism during the hyperthyroid state.

Serotonin-HPT system interaction in patients with major depression

The interaction of the 5-HT system and thyroid axis function was investigated in patients with major depression using the D-FEN stimulation test69 (Table 3). Patients with HPT system abnormalities (as indicated by a blunted TSH response to the TRH stimulation test suggesting ‘hyperactivity’ of the HPT system) had hormonal D-FEN responses comparable to those of healthy controls, while patients without HPT abnormalities showed reduced hormonal responses to D-FEN compared to controls. The authors suggested that the blunted TSH response to TRH stimulation found in a subgroup of depressed patients might be a compensatory mechanism for diminished central 5-HT activity.69

Implications for thyroid hormone modulation of mood disorder

Does the information reviewed here of the interaction of thyroid hormones with serotonergic neurotransmission, have relevance for our understanding of the mood modulating effects of thyroid hormones in the clinical setting, and can it promote our understanding of the pathophysiology and treatment of mood disorders?

The molecular mechanisms underlying the efficacy of thyroid hormone treatment in patients with mood disorders, and in patients with primary hypothyroidism who have comorbid depression, are not known. From the few studies in humans with thyroid dysfunction, there is some evidence from the neuroendocrine challenge studies that hypothyroid status is associated with a reduced 5-HT responsiveness. Furthermore, this appears to be reversible with thyroid replacement therapy.65,67 However, given the small number of studies in humans definitive conclusions cannot be drawn. Not only is the number of studies limited but the sample sizes in the studies were small and the methods employed to assess central 5-HT function varied considerably. It is also questionable whether the peripheral blood and CSF content of 5-HT and its metabolites provide an index of brain serotonergic neurotransmission,70 while neuroendocrine challenge studies provide only an indirect way of ‘probing’ central 5-HT function.71

In contrast, results from studies in animals provide strong evidence that thyroid status has a considerable impact in serotonergic neurotransmission in the adult brain. Experimentally-induced hypothyroid states result in an increase in 5-HT turnover in the brainstem. Increased 5-HT turnover in hypothyroid states may lead to an increase in raphe 5-HT1A autoreceptor activity and a decrease in cortical 5-HT concentrations (Figure 1). This observation indicates that in the raphe area increased serotonin turnover may activate inhibitory autoreceptors on the serotonergic cell bodies and thus, reduce serotonin turnover in the cortical and subcortical projection areas of these serotonergic neurons. The value of direct measurements of 5-HT and its precursors/metabolites from homogenized brain tissues is limited. However, in more recent receptor studies, it was found that hypothyroid states result in a decrease in cortical 5-HT2A receptor density, an observation that reinforces the postulate that hypothyroidism is associated with a reduced cortical serotonergic neurotransmission.

Figure 1
Figure 1

The thyroid–brain serotonin system interrelationship in adult animals. (a) Experimentally-induced hypothyroidism. (b) Effects of thyroid hormone on the brain serotonin system.

Thyroid hormone application may increase cortical serotonergic neurotransmission via two independent mechanisms: (1) by reducing the sensitivity of 5-HT1A autoreceptors in the raphe area, thus disinhibiting cortical and hippocampal serotonin release; and (2) by increasing cortical 5-HT2 receptor sensitivity, a potentially independent way of increasing 5-HT neurotransmission (Figure 1). These latter two potential mechanisms for thyroid hormone modulation of serotonin transmission warrant further elaboration. With respect to the first mechanism, it is important to note that in animal studies it has been demonstrated that an acute blockade of serotonin transporters by SSRIs increases raphe serotonin concentrations immediately.72,73 However, application of SSRIs also activates presynaptic 5-HT1A autoreceptors located on serotonergic cell bodies in the raphe area and may thus inhibit serotonin release in the cortical projection areas.23 Subsequently, an increase in frontal serotonin release is only found after prolonged SSRI application,74 when increased synaptic serotonin concentrations in the brainstem induce a down-regulation of 5-HT1A autoreceptors, or after a drug-induced blockade of 5-HT1A receptors.75 This mechanism has been postulated to be responsible for the delayed antidepressive effects of SSRIs.23 In accordance with this hypothesis, a blockade of 5-HT1A receptors would facilitate the antidepressive action of SSRIs in patients with major depression.63,76 A similar mechanism involving a desensitization of presynaptic 5-HT1A autoreceptors could be involved in the efficacy of thyroid hormones to accelerate and augment antidepressant agents. This could also explain why T3 augmentation treatment in patients with depression usually takes effect in the first 2 weeks after initiation of treatment. Thus, potential similarities exist in the putative mechanism of action of the 5-HT1A receptor antagonist pindolol and of thyroid hormones, and that both pindolol and T3 are found to speed recovery from depression.7,63,76 With respect to the potential second mechanism, it should be noted that reduced 5-HT2 receptor sensitivity has been observed in most,77,78,79,80 although not all studies of patients with major depression.81 Subsequently, treatment with clomipramine or SSRIs increased 5-HT2 receptor sensitivity.82,83 Thus, thyroid hormone-induced increases in 5-HT2 receptor sensitivity might potentiate the effects of antidepressant drugs on the 5-HT2 receptors, as has been demonstrated in studies with animals54,60 and humans.65,67 However, a hypothesis of 5-HT2 receptor-mediated antidepressive effects of thyroid hormones faces some limitations. First, the serotonin receptor subtypes perturbed in the neuroendocrine challenge studies in humans are unknown. In these clinical studies, the in vivo serotonin receptor sensitivity is indirectly assessed by measuring cortisol or prolactin release after serotonergic challenge with various drugs (5-hydroxytryptophan, fenfluramine or meta-chlorophenylpiperazine).82,83,84,85 The observed effect might be mediated via various contributions of both 5-HT2C and 5-HT1A receptor stimulation.66,86,87 Second, autoradiographic and brain imaging studies, measuring not the sensitivity but the density of 5-HT2 receptors among patients with major depression, observed significant decreases in frontocortical 5-HT2 receptor availability after antidepressive drug treatment.88,89 Of course, increases in receptor sensitivity may be accompanied by decreases in receptor number to avoid overstimulation of the monoamine neurotransmitter system and this may be the explanation. Such a hypothesis would be supported by the observation in animal studies of Heal and Smith,54 Sandrini et al58 and Watanabe61 that cortical 5-HT2 receptor density was reduced after thyroid hormone application, a procedure which has been shown to increase the sensitivity of this receptor subtype.54,60,65,67

Further considerations

Post-receptor and molecular actions of thyroid hormones

While not the primary focus of this review, other sites of thyroid hormone action that are important for understanding thyroid hormone effects on brain function, include post-receptor, transcriptional, and gene regulatory mechanisms. A series of studies indicate that these signaling pathways, downstream from receptors, are also influenced by changes in thyroid status. In rats, hypothyroidism induced a significant up-regulation of G-protein complexes in synaptosomal membranes from different brain regions.90 Conversely, in studies of euthyroid animals, treatment with T3 decreased the abundance of the alpha-subunits of Gi in synaptosomal membranes of the cerebral cortex.91 Impaired signal transduction via adenylate cyclase and inositol phosphatase has also been demonstrated in the adult brain of hypothyroid rats. Hypothyroid rats also showed enhanced inhibition of adenylate cyclase in synaptosomal membranes by GTP,92 and decreased formation of inositol phosphate in response to the muscarinic cholinergic agonist carbachol.93 Thus, it appears that thyroid hormones exert an important influence on the activity and synthesis of G-proteins and the receptor/G-coupling systems that serve the monoamine receptor system. Thus thyroid hormone deficiency leads to an impairment in adenylate cyclase activity and phosphoinositide-based signaling pathways involved in transcriptional activities in the adult CNS.16,90,91

The molecular action of thyroid hormone is mediated through specific nuclear TH receptors (TRs) α and β (β1, β2), functioning as ligand-dependent transcription factors that increase or decrease the expression of target genes.94 Although the two genes that encode the related TRα and TRβ are differentially expressed, the two receptors usually coexist in the same cell type. The relative contribution of these two TR genes encoding for TRα and TRβ in mediating a particular T3 response is poorly understood because of a lack of in vivo functional information. Knock-out mouse models lacking a particular TR isoform have been generated to explore the relative contribution of each of the TR isoforms to the TH-mediated regulation of various biological processes in different tissues. However, the animals tested to date showed little overt behavioral or neuroanatomical abnormalities compared with animals rendered hypothyroid by thyroidectomy95,96,97,98 suggesting that other TR forms may compensate or substitute for lacking or defective receptors in these knock-out mouse models. In contrast, a TR knock-in mouse model with a T3 binding mutation in the TRβ locus resulted in severe neuroanatomical and behavioral dysfunction (eg, abnormal hippocampal gene expression of brain-derived neurotrophic factor (BDNF), myelin basic protein (MBP), and tyrosine protein kinase receptor B (TrkB), learning deficiency, and cerebellar dysfunction) indicating a specific and deleterious action of unliganded TR in the brain.99  Recent studies have also indicated that the adult brain has various genetic loci that are responsive to thyroid hormones.100 Among the most extensively studied loci is RT3/neurogranin, a brain-specific gene encoding a protein kinase C substrate that binds calmodulin and is located in dendritic spines and forebrain neurons;101 in these studies, adult-onset hypothyroidism led to a decrease of RC3/neurogranin, an effect that was reversible with T4 treatment.102 Thyroid hormone also modulates glucose transport processes across the blood–brain barrier (BBB)103 and in astrocytes,104 and may alter the expression of glucose transporter one (GLUT-1) gene, the principal isoform responsible for glucose transport across the BBB.105 Furthermore, the effects of thyroid hormones on CNS gene expression have been demonstrated for various other neuroactive peptides, eg, TRH,106 corticotropin-releasing hormone (CRH),107 brain-derived neurotrophic factor, nerve growth factor and neurotrophin 3,108,109 angiotensinogen,110 and several structural brain-specific genes (eg, myelin-associated glycoprotein, Pcp-2, microtubule-associated proteins).111 Of particular relevance is a recently reported interaction between thyroid and serotonin systems, indicating synergistic effects of T3 and 5-HT1A receptors on hippocampal brain-derived neurotrophic factor (BDNF) expression. T3 administration prior to treatment with a 5-HT1A agonist caused a downregulation of hippocampal BDNF mRNA expression in adult rats.111 These molecular studies clearly indicate that thyroid hormones actively regulate a broad spectrum of genes in the adult brain although the behavioral significance of such activity is unknown.


In our review we found evidence, particularly from results in animal studies, to support the hypothesis that thyroid status impacts the serotonin system in the adult brain, and that increasing thyroid hormone levels increase serotonin neurotransmission. Given the important role of the serotonin system in the pathogenesis of depression we speculate that the serotonin system may be involved in the mood modulating effects of thyroid hormones among patients with affective disorders. This hypothesis would explain why thyroid hormones are most effective in patients with affective disorders when administered as an adjunctive treatment to antidepressants and/or mood stabilizers that perturb the serotonin system. This is also supported by evidence that thyroid hormones alone appear to have limited clinical use in affective illness.4,5

It must be emphasized however that this interaction with the serotonin system is probably only one of the mechanisms through which thyroid hormones may have modulatory effects in mood disorders. Thyroid hormones interact with a broad range of neurotransmitter systems thought to be involved in the regulation of mood including post-receptor and signal transducing processes, as well as gene regulatory mechanisms.


  1. 1.

    , . Behavioral and psychiatric aspects of thyrotoxicosis. In: Braverman LE, Utiger RD (eds). Werner and Ingbar's The Thyroid (8th edn) Lippincott-Raven: Philadelphia 2000 pp 673–678

  2. 2.

    , . Behavioral and psychiatric aspects of hypothyroidism. In: Braverman LE, Utiger RD (eds). Werner and Ingbar's The Thyroid (8th edn) Lippincott-Raven: Philadelphia 2000 pp 837–842

  3. 3.

    , . Thyroid hormone, neural tissue and mood modulation World J Biol Psych 2001 2: 57–67

  4. 4.

    , . Rapid cycling bipolar affective disorders. II. Treatment of refractory rapid cycling with high-dose levothyroxine: a preliminary study Arch Gen Psychiatry 1990 47: 435–440

  5. 5.

    , , . Treatment of intractable non-rapid cycling bipolar affective disorder with high-dose thyroxine: an open clinical trial Neuropsychopharmacology 1994 10: 183–189

  6. 6.

    , , , , , . Subjective response to and tolerability of long-term supraphysiological doses of levothyroxine in refractory mood disorders J Affect Disord 2001 64: 35–42

  7. 7.

    , , , , , et al. Does thyroid supplementation accelerate antidepressant response? A review and meta-analysis of the literature Am J Psychiatry (in press)

  8. 8.

    , , , . Triiodothyronine augmentation in the treatment of refractory depression. A meta-analysis Arch Gen Psychiatry 1996 53: 842–848

  9. 9.

    , , , . Treatment of refractory depression with high-dose thyroxine Neuropsychopharmacology 1998 18: 444–455

  10. 10.

    , . The role of thyroid hormones in prenatal and neonatal neurological development—current perspectives Endocr Rev 1993 14: 94–106

  11. 11.

    , . Thyroid hormones and brain development Eur J Endocrinol 1995 133: 390–398

  12. 12.

    , , , , . Cerebral blood flow and oxygen consumption in hyperthyroidism before and after treatment J Clin Invest 1953 32: 202–208

  13. 13.

    , , , . The cerebral circulation and metabolism in hyperthyroidism and myxedema J Clin Invest 1954 33: 1434–1440

  14. 14.

    , . Cerebral-cortex perfusion-rates in myxoedema Lancet 1968 1: 1170–1172

  15. 15.

    , , . Molecular actions of thyroid hormone. In: Braverman LE, Utiger RD (eds). Werner and Ingbar's The Thyroid (8th edn) Lippincott-Raven: Philadelphia 2000 pp 174–195

  16. 16.

    , . Thyroid hormones and the treatment of depression: an examination of basic hormonal actions in the mature mammalian brain Synapse 1997 27: 36–44

  17. 17.

    , . Nuclear triiodothyronine receptor sites in brain: probable identity with hepatic receptors and regional distribution Endocrinology 1978 103: 267–273

  18. 18.

    , , . Regional distribution of nuclear T3 receptors in rat brain and evidence for preferential localization in neurons J Endocrinol Invest 1985 8: 343–348

  19. 19.

    , . The deiodinase family of selenoproteins Thyroid 1997 7: 655–668

  20. 20.

    , , . Concentrations of thyroxine and 3,5,3′-triiodothyronine at 34 different sites in euthyroid rats as determined by an isotopic equilibrium technique Endocrinology 1985 117: 1201–1208

  21. 21.

    . Dibutyryl cAMP induction of type II 5’deiodinase activity in rat brain astrocytes in culture Biochem Biophys Res Commun 1988 151: 1164–1172

  22. 22.

    , , , , et al. Phenolic and tyrosyl ring iodothyronine deiodination and thyroid hormone concentrations in the human central nervous system J Clin Endocrinol Metab 1996 81: 2179–2185

  23. 23.

    , . Current advances and trends in the treatment of depression TIPS 1994 15: 220–226

  24. 24.

    , . Recent studies on norepinephrine systems in mood disorders. In: Bloom FE, Kupfer DJ (eds) Psychopharmacology: The Fourth Generation of Progess Raven Press: New York, NY 1995 pp 911–920

  25. 25.

    , . The serotonin hypotheses of major depression. In: Bloom FE, Kupfer DJ (eds) Psychopharmacology: The Fourth Generation of Progess Raven Press: New York NY 1995 pp 933–944

  26. 26.

    . Adrenal, medullary, and thyroid relationships Physiol Rev 1964 44: 161–185

  27. 27.

    , . A hypotheses of thyroid-catecholamine-receptor interaction Arch Gen Psychiatry 1981 38: 106–113

  28. 28.

    , . Immunohistochemical mapping of brain triiodothyronine reveals prominent localization in central noradrenergic systems Neuroscience 1996 74: 897–915

  29. 29.

    , , , . Evidence that 3,3’,5-triiodothyronine is concentrated in and delivered from the locus coeruleus to its noradrenergic targets via anterograde axonal transport Neuroscience 1999 93: 943–954

  30. 30.

    , . Structure and function of the brain serotonin system Physiol Rev 1992 72: 165–229

  31. 31.

    . The biochemistry of affective disorders Br J Psychiatry 1967 113: 1237–1264

  32. 32.

    , , , , . ’Serotonin depression‘_a biochemical subgroup within the affective disorders? Science 1976 191: 478–480

  33. 33.

    , , , , , et al. Serotonin and the neurobiology of depression. Effects of tryptophan depletion in drug-free depressed patients Arch Gen Psychiatry 1994 51: 865–874

  34. 34.

    , , . Modifications of the serotonin system by antidepressant treatments: implications for the therapeutic response in major depression J Clin Psychopharmacol 1987 7 (Suppl): 24S–35S

  35. 35.

    , , , , , . Serotonin function and the mechanisms of antidepressant action. Reversal of antidepressant induced remission by rapid depletion of plasma tryptophan Arch Gen Psychiatry 1990 47: 411–418

  36. 36.

    , , , , , , et al. Reduced serotonin transporters in alcoholism Am J Psychiatry 1998 155: 1544–1549

  37. 37.

    , , , , , et al. Reduced brain serotonin transporter availability in major depression as measured by [123I]-2-β-carbomethoxy-3β-(4-iodophenyl)tropane and single photon emission computed tomography Biol Psychiatry 1998 44: 1090–1098

  38. 38.

    , , , . Effect of neonatal hypothyroidism on the serotonin system of the rat brain Brain Res 1984 292: 99–108

  39. 39.

    , , . Brain biogenic amines and altered thyroid function Life Sci 1975 17: 1617–1626

  40. 40.

    , . Thyroid hormone control of serotonin in developing rat brain Res Commun Chem Pathol Pharmacol 1975 10: 37–50

  41. 41.

    , , , . Effects of thyroid state on serotonin, 5-hydroxyindoleacetic acid and substance P contents in discrete brain nuclei of adult rats Neuroscience 1983 10: 1399–1404

  42. 42.

    , , , , . Hypothyroidism increases serotonin turnover and sympathetic activity in the adult rat Can J Physiol Pharmacol 1991 69: 205–210

  43. 43.

    , . Streptozotocin-induced decreases in serotonin turnover are prevented by thyroidectomy Neuroendocrinology 1992 56: 354–363

  44. 44.

    , . Hypothyroid-induced changes in autonomic control have a central serotonergic component Am J Physiol 1997 272: H894–903

  45. 45.

    , , . Bulbospinal serotonergic activity during changes in thyroid status Can J Physiol Pharmacol 1998 76: 1120–1131

  46. 46.

    , , . Effect of hypo- and hyperthyroidism on regional monoamine metabolism in the adult rat brain Neuroendocrinology 1977 24: 55–64

  47. 47.

    , . Effect of L-thyroxine and carbimazole on brain biogenic amines and amino acids in rats Endocr Res 1993 19: 87–99

  48. 48.

    , , . Thyroid state and brain monoamine metabolism Endocrinology 1975 97: 1332–1335

  49. 49.

    , , . Effects of different thyroid states on 5-HT1A receptor in adult rat brain [Article in Chinese] Sheng Li Hsueh Pao 1992 44: 75–80

  50. 50.

    , , . Time course of altered thyroid states on 5-HT1A receptors and 5-HT uptake sites in rat brain: an autoradiographic analysis Neuroendocrinology 1993 57: 1011–1018

  51. 51.

    , , . Effects of experimental hypothyroidism on 5-HT1A, 5-HT2A receptors, 5-HT uptake sites and tryptophan hydroxylase activity in mature rat brain Neuroendocrinology 1999 69: 453–459

  52. 52.

    , , , , . The effects of thyroid state on beta-adrenergic and serotonergic receptors in rat brain Psychoneuroendocrinology 1987 12: 261–270

  53. 53.

    , . Influence of neonatal and adult hyperthyroidism on behavior and biosynthetic capacity for norepinephrine, dopamine and 5-hydroxytryptamine in rat brain J Pharmacol Exp Ther 1976 198: 609–618

  54. 54.

    , . The effects of acute and repeated administration of T3 to mice on 5-HT1 and 5-HT2 function in the brain and its influence on the actions of repeated electroconvulsive shock Neuropharmacology 1988 27: 1239–1248

  55. 55.

    , , , . Brain monoamine synthesis and receptor sensitivity after single or repeated administration of thyroxine J Neural Transm 1975 37: 1–10

  56. 56.

    , , , . Hyperthyroidism: specifically increased response to central NA-(alpha-)receptor stimulation and generally increased monoamine turnover in brain J Neural Transm 1977 41: 73–92

  57. 57.

    , , , , . Triiodothyronine increases desipramine by changing the concentrations of monoamines, in the brain of rats given imipramine Eur J Pharmacol 1993 231: 297–300

  58. 58.

    , , , , . Effect of acute and chronic treatment with triiodothyronine on serotonin levels and serotonergic receptor subtypes in the rat brain Life Sci 1996 58: 1551–1559

  59. 59.

    , , . Chronic clomipramine and triiodothyronine increase serotonin levels in rat frontal cortex in vivo: relationship to serotonin autoreceptor activity J Pharmacol Exp Ther 1999 288: 81–87

  60. 60.

    . Effect of acute and chronic tri-iodothyronine (T3) administration to rats on central 5-HT and dopamine-mediated behavioural responses and related brain biochemistry Neuropharmacology 1981 20: 131–144

  61. 61.

    . The influence of L-triiodothyronine on the action of desipramine on beta and serotonin 2A receptor, monoamines in rat brain [Article in Japanese] Nihon Shinkei Seishin Yakurigaku Zasshi 1999 19: 139–146

  62. 62.

    , , , , . Reduced prolactin release during immobolization stress in thyrotoxic rats: role of the central serotonergic system Horm Metab Res 1995 27: 121–125

  63. 63.

    , , . Pindolol induces a rapid improvement of depressed patients treated with serotonin reuptake inhibitors Arch Gen Psychiatry 1994 51: 248–251

  64. 64.

    , , . L-thyroxine treatment and neurotransmitter levels in the cerebrospinal fluid of hypothyroid patients: a pilot study Eur J Endocrinol 1998 139: 493–497

  65. 65.

    , , . Neuroendocrine evidence for an association between hypothyroidism, reduced central 5-HT activity and depression Clin Endocrinol (Oxf) 1995 43: 713–719

  66. 66.

    , . Pindolol treatment blocks stimulation by meta-chlorophenylpiperazine of prolactin but not cortisol secretion in normal men Psychiat Res 1995 58: 89–98

  67. 67.

    , , , , . Thyroxine replacement increases central 5-hydroxytryptamine activity and reduces depressive symptoms in hypothyroidism Neuroendocrinology 1996 64: 65–69

  68. 68.

    , , , . Biogenic amines and thyrotoxicosis Acta Endocrinol 1992 126: 315–318

  69. 69.

    , , , , , et al. Thyroid axis activity and serotonin function in major depressive episode Psychoneuroendocrinology 1999 24: 695–712

  70. 70.

    . Peripheral indices of central serotonin function in humans Ann NY Acad Sci 1990 600: 282–295

  71. 71.

    , , . Hormonal probes of central serotonergic activity? Do they really exist? Biol Psychiatry 1987 22: 86–98

  72. 72.

    , . Differential effects of clomipramine given locally or systematically on extracellular 5-hydroxytryptamine in raphe nuclei and frontal cortex: an in vivo microdialysis study Naunyn-Schmiedeberg's Arch Pharmacol 1991 343: 237–244

  73. 73.

    , . Fluvoxamine preferentially increases extracellular 5-hydroxytryptamine in the raphe nuclei: an in vivo microdialysis study Eur J Pharmacol 1992 229: 101–103

  74. 74.

    , . Chronic treatment with fluvoxamine increases extracellular serotonin in frontal cortex but not in raphe nuclei Synapse 1993 15: 243–245

  75. 75.

    . Serotonin 5-HT1A autoreceptor blockade potentiates the ability of the 5-HT reuptake inhibitor citalopram to increase nerve terminal output of 5-HT in vivo: a microdialysis study J Neurochem 1992 60: 776–779

  76. 76.

    . Pindolol, 5-hydroxytryptamine, and antidepressant augmentation Arch Gen Psychiatry 1995 52: 969–971

  77. 77.

    , , . Reduced prolactin and cortisol responses to d-fenfluramine in depressed compared to healthy matched control subjects Neuropsychopharmacology 1996 14: 349–354

  78. 78.

    , , , , , . Neuroendocrine and behavioral responses to intravenous m-chlorophenylpiperazine (mCPP) in depressed patients and healthy comparison subjects Am J Psychiatry 1994 151: 1626–1630

  79. 79.

    , . Prolactin and cortisol responses to d-fenfluramine in major depression: evidence for diminished responsivity of central serotonergic function Am J Psychiatry 1991 148: 1009–1015

  80. 80.

    , , , , . Plasma cortisol, prolactin, growth hormone, and immunoreactive beta-endorphin response to fenfluramine challenge in depressed patients Clin Neuropharmacol 1988 11: 250–256

  81. 81.

    , , . 5-HT neuroendocrine function in major depression: prolactin and cortisol responses to d-fenfluramine Psychol Med 1996 26: 1191–1196

  82. 82.

    , , , . Fluoxetine, but not tricyclic antidepressants, potentiates the 5-hydroxytryptophan-mediated increase in plasma cortisol and prolactin secretion in subjects with major depression or with obsessive compulsive disorder Neuropsychopharmacology 1997 17: 1–11

  83. 83.

    , , . Clomipramine enhances the cortisol response to 5-HTP: implications for the therapeutic role of 5-HT2 receptors Psychopharmacol (Berl) 1998 140: 120–122

  84. 84.

    , , . D-fenfluramine-induced prolactin and cortisol release in major depression: response to treatment J Affect Disord 1992 26: 143–150

  85. 85.

    , , , , , et al. Effects of meta-chlorophenylpiperazine infusions in patients with seasonal affective disorder and healthy control subjects. Diurnal responses and nocturnal regulatory mechanisms Arch Gen Psychiatry 1997 54: 375–385

  86. 86.

    , , , , , . Serotonin function in human subjects: intercorrelations among central 5-HT indices and aggressiveness Psychiatry Res 1997 73: 1–14

  87. 87.

    , . Effect of pindolol on hormone secretion and body temperature: partial agonist effects J Neural Transm 1996 103: 77–88

  88. 88.

    , , , , , . 5-HT2 receptor changes in major depression Biol Psychiatry 1990 27: 489–496

  89. 89.

    , , , , , et al. Decrease in brain serotonin 2 receptor binding in patients with major depression following desipramine treatment Arch Gen Psychiatry 1999 56: 705–711

  90. 90.

    , , , . Abundance of the alpha-subunits of Gi1, Gi2 and Go in synaptosomal membranes from several regions of the rat brain is increased in hypothyroidism Biochem J 1991 275: 183–186

  91. 91.

    , , , . Treatment with triiodothyronine decreases the abundance of the alpha-subunits of Gi1 and Gi2 in the cerebral cortex J Neurol Sci 1992 112: 34–37

  92. 92.

    , . Inhibition of adenylate cyclase in rat brain synaptosomal membranes by GTP and phenylisopropyladenosine is enhanced in hypothyroidism Biochem J 1989 263: 829–835

  93. 93.

    , , , , , . Hypothyroidism inhibits the formation of inositol phosphate in response to carbachol in the striatum of adult rat Res Commun Chem Pathol Pharmacol 1991 73: 173–180

  94. 94.

    . The molecular basis of thyroid hormone action N Engl J Med 1994 29: 847–853

  95. 95.

    , , , , , et al. Recessive resistance to thyroid hormone in mice lacking thyroid hormone receptor beta: evidence for tissue-specific modulation of receptor function EMBO J 1996 15: 3006–3015

  96. 96.

    , , , , , et al. The T3R alpha gene encoding a thyroid hormone receptor is essential for post-natal development and thyroid hormone production EMBO J 1997 16: 4412–4420

  97. 97.

    , , , , , et al. Abnormal heart rate and body temperature in mice lacking thyroid hormone receptor alpha 1 EMBO J 1998 17: 455–461

  98. 98.

    , , , , , et al. Mice devoid of all known thyroid hormone receptors are viable but exhibit disorders of the pituitary-thyroid axis, growth, and bone maturation Genes Dev 1999 13: 1329–1341

  99. 99.

    , , , , , et al. An unliganded thyroid hormone receptor causes severe neurological dysfunction Proc Natl Acad Sci USA 2001 98: 3998–4003

  100. 100.

    . Thyroid hormone metabolism and action in the brain and pituitary Acta Med Austriaca 2000 27: 1–7

  101. 101.

    , , , , . Influence of thyroid hormone on brain gene expression Acta Med Austriaca 1992 19 (Suppl 1): 32–35

  102. 102.

    , , , , . Adult rat brain is sensitive to thyroid hormone. Regulation of RC3/neurogranin mRNA J Clin Invest 1991 90: 554–558

  103. 103.

    . Metabolic fuel and amino acid transport into the brain in experimental hypothyroidism Acta Endocrinol (Copenh) 1990 122: 156–162

  104. 104.

    , , , , . Thyroid hormone action on glucose transporter activity in astrocytes Biochem Biophys Res Commun 1988 156: 275–281

  105. 105.

    , , . Brain-type glucose transporter (GLUT-1) is selectively localized to the blood–brain barrier. Studies with quantitative western blotting and in situ hybridization J Biol Chem 1990 265: 18035–18040

  106. 106.

    , , , , , , . Thyroid hormone regulates (TRH) biosynthesis in the paraventricular nucleus of the rat hypothalamus Science 1987 238: 78–80

  107. 107.

    , , . Response of hypothalamic peptide mRNAs to thyroidectomy Neuroendocrinology 1992 56: 694–703

  108. 108.

    , , , , . Thyroid hormone regulation of NGF, NT-3 and BDNF RNA in the adult rat brain Mol Brain Res 1992 16: 239–245

  109. 109.

    , , , , . Expression of neurotrophins and the trk family of neurotrophin receptors in normal and hypothyroid rat brain Brain Res Mol Brain Res 1994 27: 249–257

  110. 110.

    , . Effects of thyroid hormones on angiotensinogen gene expression in rat liver, brain, and cultured cells Endocrinology 1992 130: 1231–1237

  111. 111.

    , , , , . Influence of thyroid hormone on 5-HT1A and 5-HT2A receptor-mediated regulation of hippocampal BDNF mRNA expression Neuropharmacology 2001 40: 48–56

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We thank Georg Juckel, MD, and Faustino Lopez-Rodriguez, PhD, MD, for comments on the manuscript. This work has been supported by a grant from the Deutsche Forschungsgemeinschaft to MB (Ba 1504/3–1).

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  1. University of California Los Angeles (UCLA), Neuropsychiatric Institute & Hospital, Department of Psychiatry and Biobehavioral Sciences, 760 Westwood Plaza, Los Angeles, CA 90024, USA

    • M Bauer
    •  & P C Whybrow
  2. Central Institute of Mental Health, Department of Addictive Behavior and Addiction Research, 68159 Mannheim, Germany

    • A Heinz


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