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Molecular Psychiatry (2002) 7, 140–156  2002 Nature Publishing Group All rights reserved 1359-4184/02 $25.00 www.nature.com/mp REVIEW ARTICLE , and mood: of synergy and significance in the adult M Bauer1, A Heinz2, and PC Whybrow1

1University of California Los Angeles (UCLA), Neuropsychiatric Institute & Hospital, Department of Psychiatry and Biobehavioral Sciences, 760 Westwood Plaza, Los Angeles, CA 90024, USA; 2Central Institute of Mental Health, Department of Addictive Behavior and Addiction Research, 68159 Mannheim, Germany

The use of 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 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 con-

sistently reported while decreased cortical 5-HT concentrations and 5-HT2A density are less frequently observed. In the majority of studies, the effects of thyroid admin- istration 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 sensi- tivity. 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. Molecular Psychiatry (2002) 7, 140–156. DOI: 10.1038/sj/mp/4000963

Keywords: thyroid system; T4;T3; serotonin system; adult brain; 5-HT receptor; mood modulation; affective disorders; depression

Introduction Thyroid supplementation is now widely accepted as an effective treatment option for patients with affective The thyroid system and mood modulation in disorders.7–9 affective illness Disorders of the thyroid gland are frequently associated with severe mental disturbances.1,2 This intimate Actions of thyroid hormones in the adult brain association between the thyroid system and behavior It is well established that thyroid hormones are essen- has been the impetus for exploring the effects of thy- tial for both the development and maturation of the roid hormones in modulating affective illness, and the human brain, affecting such diverse events as neuronal role of the hypothalamic-pituitary thyroid (HPT) axis processing and integration, glial proliferation, in the pathophysiology of mood disorders.3 Thyroid myelination, and the synthesis of key hormones (TH) have a profound influence on behavior required for neurotransmitter synthesis.10,11 Thyroid and mood, and appear to be capable of modulating the deficiency during the perinatal period results in irre- phenotypic expression of major affective illness.3–6 versible brain damage and mental retardation. How- ever, despite this accepted body of knowledge and in disregard of the clinical and therapeutic observations Correspondence: M Bauer, MD, PhD, Department of Psychiatry in association with affective illness, the action of thy- and Biobehavioral Sciences, University of California Los Angeles roid hormones in CNS function in adults has not been (UCLA), 300 Medical Plaza, Suite 2330, Los Angeles, CA 90095, USA. E-mail: [email protected] widely acknowledged by general endocrinologists. Received 14 March 2001; revised 7 June 2001; accepted 15 This lack of interest seems to have originated in the June 2001 1950s and 1960s, when early physiological studies sug- Thyroid serotonin relationship M Bauer et al 141 gested that oxygen consumption in the mature human interaction derives largely from immunohistochemical 12–14 brain did not change with changing thyroid status. mapping studies demonstrating that T3 is concentrated Thus, in contrast to our understanding of thyroid in both nuclei and projection sites of central NA sys- 28 hormone’s critically important role in the development tems. Recent evidence that T3 is also delivered from of the CNS, until recently, little has been known about the locus coeruleus to its NA targets via anterograde the function and effects of thyroid hormones in the axonal transport indicates that T3 may function as a mature mammalian brain.15 However, with improved cotransmitter with in the adrenergic methods in basic research the action of thyroid hor- nervous system.29 mones in the mature brain has become a subject of However, the neuropharmacological effects and greater interest.16 There are several lines of evidence functional pathways underlying the therapeutic effects suggesting that thyroid hormones affect mature brain of thyroid hormones in patients with affective dis- function. First, thyroid hormone receptors are preva- orders are still unclear. One of the most intuitive lent in the mature brain. Nuclear receptors for T3, the hypotheses postulates the existence of a brain thyroid thyroid hormone with the highest biological activity, hormone deficiency in affective illness. Thyroid hor- are widely distributed in adult rat brain with higher mone therapy can then be considered a replacement densities of nuclear T3 receptors in phylogenetically therapy with a possible mechanism of action being its younger brain regions—in the amygdala and hippo- pharmacological effects on monoamine neuro- campus—and lower densities in the brain stem and transmitter systems, eg, by increasing ␤-adrenergic cerebellum.17,18 A second line of evidence pertains to receptor activity and thus promoting the action of cat- brain thyroid hormone . The process of 5- echolamines at central receptor sites.27 deiodination by which both thyroid hormones, T4 and T , are metabolized to inactive iodothyronines has 3 The CNS serotonin system been demonstrated to be different in the adult brain As with the noradrenergic and dopaminergic systems, from that in peripheral tissues. Specifically, the type the bulk of the CNS serotonergic nerve terminals orig- D2 and type D3 catalyze these metabolic inate in the neuronal cell bodies of the brainstem raphe processes in spatially distinct patterns in the central nuclei and project, both rostrally and caudally, to neu- nervous system and appear to be segregated into spe- roanatomically discrete areas throughout the brain but cific cell types.19 D2 is expressed primarily in the brain with extensive innervation of the cerebral cortex and and gland where it metabolizes T to 4 the limbic system.30 Although the serotonin system has the active thyroid hormone form, T . The activity of D2 3 been given prominence in recent deliberation regard- in distinct regions of the brain varies widely, with the ing mood modulation, particularly since the advent of highest levels found in cortical areas and lesser activity that specifically interfere with serotonin neu- in the midbrain, pons, and brainstem.20 ronal reuptake systems, there has been little investi- In rat brain D2 is expressed in , in particular gation of the relationship of this system to the thyroid in the nerve terminals, but also in astrocytes.21 Third, system. This paper analyzes the existing literature per- thyroid hormones have been detected in relatively high taining to this relationship and explores areas which (nanomolar) concentrations in cortical tissue.22 In con- may be fruitful for further study. trast to peripheral tissue where T4 concentrations usu- ally far exceed those of T3, in the brain T4 and T3 con- centrations are in an equimolar range. The brain serotonin system and its role in depression Basic and clinical research of the past three decades Monoamines and mood has yielded compelling evidence that the serotonergic Over the past two decades it has become apparent that system is intimately involved in the pathogenesis of the monoamines, specifically norepinephrine and sero- depression.23,25,31,32 Changes in serotonergic neuro- tonin play a major role in mood modulation.23–27 These transmission have been repeatedly associated with the long track systems which begin in the brainstem and therapeutic response to and mood stabi- extend through the midbrain into the limbic system lizing .23,33 Almost all currently employed and cortex modulate the activity of many of the brain treatments for depression, including the tricyclic anti- regions related to emotion and memory. The inter- , the SSRIs, the MAO inhibitors, dependence of these long tracks—including the dopa- and ECT, directly or indirectly augment serotonergic mine system—with thyroid hormone metabolism has neurotransmission.34 Another line of evidence derives become better understood as our technology has from the tryptophan-depletion paradigm, a procedure improved. that lowers central serotonin levels, and which The catecholaminergic system was initially investi- produces a rapid relapse of SSRI-responsive gated largely because of the known physiological depression.33,35 Other support comes from studies association between sympathetic activity and thyroid demonstrating lowered levels of 5-hydroxyindoleacetic hormones.26 Thyroid hormones appear to play an acid (5-HIAA), a metabolite of 5-HT whose levels important role in regulating central noradrenergic (NA) reflect central serotonin activity, in the CSF in unmedi- function and it has been suggested that thyroid dys- cated depressed patients.25 In brain imaging studies, function may be linked with abnormalities in central clinical depression was associated with reduced sero- NA neurotransmission.27 Evidence for a thyroid–NA tonin transporter availability.36,37

Molecular Psychiatry Thyroid serotonin relationship M Bauer et al 142 Objectives and elements of this review induced by daily application of T3 This article explores the hypothesis that the mood also resulted in an increased turnover of 5-HT.39 modulating activity of thyroid hormones may be mediated in part by interaction with the brain sero- Measurements of 5-HT and its metabolites in adult tonin system, specifically by enhancing cortical sero- hypothyroid animals In the adult rat brain, hypothy- tonergic neurotransmission. Because of the specific roidism generally induced lesser changes in the sero- organization of the brain serotonin system, an analysis tonergic system compared to the studies in neonatal of the literature has been divided into anatomical animals. Thirteen studies were identified that meas- areas: specifically the brainstem, the midbrain, the lim- ured the effects of experimentally-induced hypothy- bic system, and the cortex; those studies that were not roidism on the serotonergic system. The methods and specified in regard to brain area, as were many of the results of these studies are shown in Table 1. One early early studies, are referred to as ‘whole brain studies’. study measured brainstem 5-HT concentrations and The other important element running through these did not find significant differences compared to euthy- analyses is the technical advance which has occurred roid animals.40 Later, using more sensitive assay tech- over the 25 years that are the subject of our review. niques, five studies measured 5-HT and 5-HIAA con- Specifically, many early studies were based upon centration or the 5-HIAA/5-HT ratio as an indicator of crude analyses of levels of serotonin and its metab- the serotonin turnover and reported increased 5-HT olites in homogenized brain tissue of animals that had metabolites in the brainstem41–45 (notice: one study cal- been previously exposed to hypo- or hyperthyroid culated the inverse ratio, 5-HT/5-HIAA41). Reduced 5- states. As technology advanced and our chemical dis- HT concentrations in the cortex,46,47 and reduced con- section of thyroid hormone system metabolism gained centrations of the serotonin precursor 5-HTP were specificity, more sophisticated studies emerged that reported in the whole brain48 of hypothyroid adult rats. have improved our understanding of turnover and These findings of increased 5-HT turnover in the brain- receptor activity. In the 1990s, studies and stud- stem and decreased levels of 5-HT and its precursors ies of transporter systems began to complement the in the cortex/whole brain are in accordance with the earlier studies, and most recently, microdialysis tech- hypothesis that increased brainstem 5-HT turnover

niques have provided new insights by measuring levels might activate raphe 5-HT1A autoreceptors and sub- of serotonin in vivo. We have tried to reflect this techni- sequently decrease serotonin release in the cortical cal advance in the analysis of the papers that are projection areas.23 reviewed.

Receptor studies: changes in 5-HT1A and 5-HT2 recep- tors in the adult hypothyroid brain Among the many Methods of literature research 5-HT receptor subtypes with different regional distri- An attempt was made to identify all reports studying butions throughout the CNS, it is the 5-HT1A and 5- the interaction between thyroid hormones and the HT2 receptor densities that have been most studied in brain serotonergic system both in animals and in experimentally-induced hypothyroid animals. The 5- humans, but with a focus on studies in the adult brain. HT1A receptor subtype, predominantly located on the A computer-aided search of the National Library of cell bodies and dendrites of the serotonergic neurons Medicine MEDLINE database for 1966 to August 2000 in the raphe nuclei, functions as a control point of using the subject headings ‘thyroid hormones’, ‘sero- activity for these neurons. In contrast, the postsynaptic tonin’, ‘brain’ and ‘affective disorders’ was performed, entities of 5-HT neurotransmission consist of several supplemented by the bibliographies of reports ident- subtypes of 5-HT2 receptors located in distinct projec- ified. tion areas of the 5-HT neurons. In experimentally-induced hypothyroid states the 5-

HT1A (presynaptic) receptor density in the brainstem Results of the review and midbrain was not altered49–52 (Table 1). Studies on the density of 5-HT1A (postsynaptic) receptors outside Effects of experimentally-induced hypothyroid states the brainstem yielded contradictory results. An on brain serotonin system in animals increase in cortical and hippocampal 5-HT1A (postsynaptic) receptors was observed by Tejani-Butt et Historical perspective: studies in neonatal animals Sti- al50 but not by Hong et al49 and Kulikov et al,51 who mulated by the essential role of thyroid hormones in found no significant differences compared to euthyroid brain development, the effects of on adult rodents. serotonergic neurotransmission were originally studied An early study by Mason et al52 found a decrease in

in neonatal rats. In these studies, 5-hydroxytryptamine 5-HT2 receptor density in the striatum but not in the (5-HT, serotonin) and 5-HIAA, the main 5-HT metab- cortex of hypothyroid adult rats. However, when 5-

olite, were found to be significantly elevated and the HT2A receptors were assessed selectively in severely serotonin precursor 5-hydroxytryptophan (5-HTP) to hypothyroid rats, a significant cortical reduction was be decreased compared to euthyroid controls indicat- recently reported by Kulikov et al.51 ing an increased serotonin turnover rate in the neonatal Hence in summary, several lines of evidence indicate period.38 Other data have demonstrated that neonatal that an experimentally-induced hypothyroid state in

Molecular Psychiatry Thyroid serotonin relationship M Bauer et al

) 143 continued ( ↓ → c 2 striatum 5-HT → 1A n.d.n.d.n.d. n.d. n.d. n.d. hippocampus, hypothalamus, striatum ↓ ↓↓ ↓ ↓ → ↓ ↑ ↓ ↓ ↑ ↑ ↓ mesodiencephalon n. preopticus med. and↓ lat. n. lat. hypothalamus infundibulum medial forebrain bundle n.d. cortex, n.d. (3) 5-HT: spinal cord hypothalamus 5-HTT, 5-HIAA/5-HT, 5- 5-HT → 1A ↑ ↑ ↓↓ ↓ ↓ ratio:n. dorsalisraphe n. medianus raphe ratio:rostral terminalis brainstem n. interstitialis striae spinal cord Levels of 5-HTand metabolites Receptors Levels of 5-HT and metabolites Receptors 5-HTT,5-HIAA/5-HT,5-HTP levels, TPH activity 5-HT → HTP levels, TPH activity (3) 5-HT: brainstem PCPA, 2 wks brainstem 35 days n.d. n.d. n.d. n.d. cortex + 6 wks 5-HT: brainstem n.d.– 5-HT: basal ganglia – hypothyroidism (2) METH, 2 wks(3) TXT HIAA/5-HT: spinal cord b Species/method Treatment to achieve Brainstem/midbrain (raphe area) Whole brain, cortex, limbic system (outside raphe area) Rat (1)Rat TXT, (1) 25 daysRat (2) TXT, 3 wks PTU, 42 days n.d.Rat (3) n.d.Rat 5-HT/5-HIAA (2) n.d. TXT, 21 n.d. TXT, 3 wks n.d. 5-HTP: whole brain 5-HT/5-HIAA ratio:Rat (3) 5-HT: cortex 5-HIAA/5-HT n.d. PTU, 2 wks n.d. 5-HIAA/5-HT ratio: n.d. n.d. n.d. Brainstem n.d. 42 41 52 48 49d Effects of experimentally-induced hypothyroid states on brain serotonin system 46 et al et al 43 et al et al a 40 et al et al Table 1 Author Jacoby Schwark &Keesey Rat (1)Savard TXT, 4 Mason Henley Henley &Bellush Rat (2) (1) TXT, 2 wks (1) and (2) 5- n.d. (1) and (2) 5-HIAA/5-HT: n.d. n.d. Ito Hong

Molecular Psychiatry Thyroid serotonin relationship M Bauer et al - 144 = p = ↓ 5-hydroxy- ↓ = : c 2 2A (3) autonomic – 5-HT (cardiovascular) response 5-HT frontal cortex microdialysis/HPLC, 8 = → → ↑ ↑ 1A n.d. n.d. hippocampus hippocampus hypothalamus HPLC (high-performance liquid chromatography), → 8-hydroxy-2-(di-n-propylamino)tetralin; PCPA = 5-hydroxytryptamine (serotonin); 5-HTP → = = radioimmunoassay (RIA), 7 = . ↓ → → ↓ = ↑ uorometry, 2 fl 5-HTT: hippocampus cortex, hypothalamus,hippocampus cortex 5-HTT, 5-HIAA/5-HT, 5- 5-HT hypothalamus TPH: hippocampus Frontal cortex nucleus; 8-OH-DPAT = → → 1A not done. 5-hydroxyindoleacetic acid; 5-HT = = tryptophan hydroxylase; TXT = behavioral response experiments, 6 Methimazole; n. = = ↑ ↑ Liquid chromatography/(spectro-) → = → .1 cant change; n.d. fi Levels of 5-HTand metabolites Receptors Levels of 5-HT and metabolites Receptors → 5-HTT,5-HIAA/5-HT,5-HTP levels, TPH activity 5-HT n. dorsalisraphe HTP levels, TPH activity raphe in vivo receptor binding, 5 ; TPH no signi = = 5-HT1A 5-HIAA 5-HT2 5-HT brainstem → + + in vitro 2,5-dimethoxy-4-iodoamphetamine; 5-HIAA = cant decrease; -free diet, 24 days midbrain fi (2) PTU, 3 wks(3) METH, 3 wks HIAA/5-HT brainstem spinal cord hypothyroidism (2) METH, 3 wks (8-OH-DPAT)(3) METH, 3 wks agonist (DOI) brainstem + autoradiographic : DOI signi , homogenized brain tissue, (7) = = b ↓ hydroxytryptamine (serotonin) transporter; METH in vitro = = Species/method Treatment to achieve Brainstem/midbrain (raphe area) Whole brain, cortex, limbic system (outside raphe area) Rat (2)Rat (1) (3) TXT, 3 wks TXT, 7 days (1) to (3): 5- n.d. 5-HTT & TPH: midbrain (1) to (3): 5-HIAA/5-HT n.d. n.d. Rat (5) TXT, 7, 14 and 35 days 5-HTT: n. dorsalis 5-HTT: day 7 and 35: n.d. 4,6) 51 – 45 et Continued cant increase; et al 47 fi et al : neocortex, basal ganglia, olfacto-limbic areas, spinal cord. a 44 2A radioligand binding, 4 signi = 50 = Only abstract available. Methods: (1 In order of the year published. 5-HT Agrawal tryptophan; 5-HTT Table 1 Author Upadhyaya & Rat (4) , 15 days n.d. n.d.a b 5-HT: cortex c d Kulikov Henley ↑ Non-Standard Abbreviations chlorophenylalanine (5-HT synthesis blocker); PTU neuroendocrine test. 3 Tejani-Butt al Henley &Vladic Rat (2) (1) METH, 3 wks (2) and (3): n.d. n.d. n.d. (1)

Molecular Psychiatry Thyroid serotonin relationship M Bauer et al 145 adult rodents is associated with an increased 5-HT pronounced after repeated (chronic) thyroid hormone turnover rate in the brainstem, but not with a change application. Similar studies investigating the effects on in 5-HT1A autoreceptor density in the raphe area. There 5-HT levels in the brainstem and midbrain are less con- is also some evidence that hypothyroid states result in sistent (Table 2). a decrease in cortical 5-HT serotonin concentrations and 5-HT2A receptor density. Effects of thyroid hormones on 5-HT1A receptor density and sensitivity Three autoradiographic studies have Effects of thyroid hormone application on brain reported that thyroid hormone application induces no serotonin system in animals significant reduction in raphe and midbrain 5-HT1A receptor density.49–51 However, a recent study by Gur et Fourteen studies were located that measured the acute 59 al indicated a loss of autoinhibitory 5-HT1A receptor effects of thyroid hormone (T3 and/or T4) on 5-HT 59 sensitivity mediated by T3 (Table 2). Gur et al, for the and/or L-tryptophan, 5-hydroxytryptophan (5-HTP), first time in the study of the 5-HT-thyroid interaction, and 5-HIAA concentrations in adult rodent brain (for used an in vivo microdialysis technique that allows the methods and results see Table 2). measurement of 5-HT concentrations in the brain with a high degree of accuracy in the living animal. In this Acute effects of thyroid hormones on levels of 5-HT study, the decrease in hippocampal and cortical sero- and its metabolites in the brainstem and mid- tonin release that follows the application of a 5-HT1A brain Rastogi and Singhal53 observed an increase in agonist via the activation of inhibitory autoreceptors the 5-HT precursor L-tryptophan (L-TP), and Heal and was significantly reduced by T3 alone, or T3 combined Smith54 found an increase in both 5-HT and 5-HIAA in with administration in euthyroid rats.59 the midbrain after T3 application in euthyroid animals. In contrast, Henley et al42,45 examined animals after Effects of thyroid hormones on 5-HT2 receptor density thyroidectomy, which resulted in an elevated sero- and sensitivity The database concerning changes in 5- tonin turnover rate; in these animals, T3 replacement HT2 receptor density after thyroid hormone application resulted in a significant decrease in the 5-HIAA/5-HT reveals contradictions. Mason et al52 observed an ratio in the brainstem. In the two studies of thyroid increase in 5-HT2 receptor density in the striatum, hip- replacement after thyroidectomy, T3 replacement for pocampus and cortex of thyroidectomized rats only longer than 3.5 days reduced the 5-HT turnover in cau- after long-term application of a relatively high dose of dal brainstem to completely normal values. The ␮ −1 either T3 (250–1000 gkg for 7–10 days) or T4 (250– activity of tryptophan hydroxylase (TPH), the rate-lim- 500 ␮gkg−1 for 7–10 days). Kulikov et al51 showed that iting in the synthesis of 5-HT, was found T4 application in thyroidectomized animals returned unaltered in the midbrain after T application.51,53 3 cortical 5-HT2A receptor densities to normal levels, irrespective of whether a replacement or high T4 dose ␮ −1 ␮ −1 Acute effects of thyroid hormones on levels of 5-HT was applied (15 gkg vs 200 gkg T4 for 21 days and its metabolites in cortex and whole brain More each). Lower doses and shorter duration of T3 appli- consistent than the effects of ‘micro-dissection’ cation yielded different results: Sandrini et al58 found reported above were the results of studies that meas- no significant effect on 5-HT2 receptor density in the ured the effects of thyroid hormone on levels of 5-HT hippocampus and a decrease in cortical 5-HT2 receptor and its metabolites in the cortex or in the whole brain. density after application of T3 in euthyroid rats Thyroid hormone application to euthyroid rodents (100 ␮gkg−1 for 3–7 days). In the study of Heal and 54 increased cortical or whole brain 5-HT, 5-HTP and 5- Smith the same T3 dose applied to euthyroid rats 41,46–48,54–59 ␮ −1 HIAA concentrations in 10 studies. These (100 gkg for 10 days) also decreased cortical 5-HT2 results indicating increased cortical 5-HT turnover receptor density. A reduction in prefrontal 5-HT2A were consistent despite changing technologies over a receptors was observed after coadministration of T3 25-year period, and may be considered robust. In only and the antidepressant .61 one study did the whole brain 5-HT level not increase A thyroid hormone-induced change in receptor sen- 60 after thyroid hormone administration. sitivity was observed for cortical 5-HT2 receptor func- tion in adult euthyroid rats. Heal and Smith54 observed

Chronic effects of thyroid hormones on levels of 5-HT an increase in 5-HT2 receptor sensitivity after short- 60 and its metabolites in cortex and whole brain Fewer term T3 application, and Atterwill reported similar studies assessed the effects of a single vs multiple T3 findings after both short- and long-term T3 application or T4 application on cortical serotonergic neuro- (Table 2). Under stress conditions, on the other hand, 54,55,58,59 ␮ −1 transmission in euthyroid rodents (Table 2). In administration of high doses of T4 (350 gkg for 7 three of four studies, increases in cortical or whole days) resulted in a blunting of the immobilization brain 5-HT, 5-HTP and 5-HIAA contents were observed stress-induced activation of hypothalamic 5-HT2 recep- only after repeated (chronic) thyroid hormone appli- tors.62 cation.54,55,59 Thus, the increased concentration of 5-HT and its Effects of low vs high doses of thyroid hormones on the precursors and metabolites in the cortex or whole brain 5-HT system Some studies compared the effects of a that were observed in the majority of studies were more low (replacement) vs a high dose of thyroid hormone

Molecular Psychiatry Thyroid serotonin relationship M Bauer et al

146 ) Continued ↑↑ ( c 2 (5) hyperactivity – response 5-HT 1A n.d. n.d. n.d. n.d. n.d. n.d. n.d. (2) ↑ ↑ ↓ ↑ → ↑ ↑ , cortex ↑ ) ↑ ↑ ↑ ↓ ↓ ↑ 5-HIAA: cerebellum, striatum hippocampus ( n. amygdaloideus basalis pars lat. area ventralis tegmenti n. preopticus medialis 5-HTT, 5-HIAA/5-HT, 5- 5-HT 1A n.d. 5-HT: cerebellum, n.d. n.d. ↑ → Levels of 5-HTand metabolites Receptors5-HTT,5-HIAA/5-HT,L-TP, Levels 5-HTP of 5-HTlevels, and TPH activity 5-HT metabolites HTP L-TP, 5-HTP levels, TPH activity Receptors 5-MeODMT) + , s.c.), 10 days, s.c.) n.d., s.c.), , s.c.), n.d., s.c.), (1) 5-HT: whole brain 1 1 1 1 1 , i.p.),, s.c.), n.d. L-TP: midbrain n.d. 5-HTP: whole brain , s.c.), n.d. n.d. 5-HT/5-HIAA ratio: n.d. n.d. 4 injections n.d. n.d. more than 1 injection: n.d. n.d. − − − − − 1 1 1 – − − − , s.c.), 17 days n.d. n.d. 5-HT: cortex 1 − ,1 , 4 injections s.c.), n.d. n.d. 5-HTP: striatum gkg gkg gkg gkg gkg 1 1

− − ␮ ␮ ␮ ␮ ␮ MAOI (TCP) and L-TP 5-HT agonist gkg

g 100 g g 100 g ␮ g 100 g + + MAOI (TCP) and L-TP 5-HT agonist (

␮ ␮ ␮ + + 25 days (2) T3 (100 (4) T3 (100 (quipazine or TCP s.c.), 12 h interval30 days12 h interval TPH: midbrain 5-HTP: whole brain striatum limbic system 14 days n. medialis habenulae 1 day 10 days 1 day 10 days (3) T3 (100 or 5-MeODMT) (5) T3 (100 b Mouse (1) T4 (1 mg kg Mouse (1) T4 (1 mg kg Species/method Thyroid hormone treatment Brainstem/midbrain (raphe area) Whole brain, cortex, limbic system (outside raphe area) Rat (1) T4 (15 Rat (1)Rat T4 (1,3,6) (400 (1) T3 (100 Rat (2) T4 (50 41 48 et et Effects of thyroid hormone application on brain serotonin system 60 46 et al 53 m et al a ¨ mbom et al ¨ 55 56 Table 2 Author Engstro Savard Jacoby Stro Rastogi & Rat (1) T3 (10 al Atterwill Singhal al Ito

Molecular Psychiatry Thyroid serotonin relationship M Bauer et al

) 147 (250 g) → ↑ (250, ␮ ↑ ; (2) (500, ↑ → ↑ → Continued ( → (500 g) ↓ ↑ c g) ␮ 2 ␮ g) 5-MeODMT-induced (1) receptor sensitivity (2) receptor sensitivity n.d. cortex 500 (4) cortex 1000 cortex striatum hippocampus hippocampus (2) striatum 5-HT ␮ ↑ → ↓ 1A ↓ → 2) n.d. n.d. 1) : (1) cortex cortex hypothalamus, striatum ↑ → → ↑ → ↑ n.d. hippocampus 5-HIAA: forebrain 5-HT: whole brain → forebrain 5-HTT, 5-HIAA/5-HT, 5- 5-HT → 1A ↑ ↑ ) → ↓ (2) 5-HT, 5-HIAAmid/hindbrain 5-HT and 5-HIAA: whole brain head-twitches: restored ( (normalized after TXT) n.d. n.d. n.d. n.d. (1) and (3) cortex, Levels of 5-HTand metabolites Receptors5-HTT,5-HIAA/5-HT,L-TP, Levels 5-HTP of 5-HTlevels, and TPH activity 5-HT metabolites HTP L-TP, 5-HTP levels, TPH activity Receptors g

g ␮

␮ 500 1000 , s.c.), 3.5 5-HIAA/5-HT: n.d. 5-HIAA/5-HT: spinal cord n.d. n.d. – – , i.p.), 10 1 1 , i.p.), 10 − − 1 − , s.c.),, s.c.), (1) 5-HT: 5-HIAA: n.d. (1) 5-HT & 5-HIAA: (2) 5-HT: forebrain 8-OH-DPAT Receptor density: (250 (250 1 1 − − ’ ’ gkg gkg

␮ gkg ␮

␮ , s.c.), 5 days n.d. n.d. 5-HIAA: whole brain 1 gkg gkg 10 days 10 days −

␮ ␮ – – 100 50 – – gkg high dose high dose ␮ T3 (100 ‘ ‘ + + d , i.p.), 7 , i.p.), 7 1 1 − − (1) T4 (50 wks 10 days mid/hindbrain days brainstem days (2) T4 days 1 day(2) T3 (100 midbrain kg (4) T3 kg (3) T3 (15 b Species/method Thyroid hormone treatment Brainstem/midbrain (raphe area) Whole brain, cortex, limbic system (outside raphe area) Rat (3) TXT Mouse (2,3) (1) T3 (100 Rat (2) TXT Rat (3) T3-induced hyperthyroidism, 2Rat (2) n.d. T3 (25 brainstem 54 42 57 52 49d Continued et al et al et al a et al Table 2 Author Mason Henley Hong Suzuki Heal & Smith

Molecular Psychiatry Thyroid serotonin relationship M Bauer et al

148 ) → ↓ ↓ Continued ( c 2 stress-induced activation frontal cortex hippocampus 5-HT , ↑ ), ↑ ↑ → ↑ → 1A dentate gyrus cortex: restored ( hippocampus CA1 and dentate gyrus hypothalamus n.d. n.d. frontal cortex hippocampus (2) 7 and 28 days: ↑ ↑ ↑ → → → → ↑ → ↓ hippocampus hippocampus 5-HTT, 5-HIAA/5-HT, 5- 5-HT → 1A raphe ↓ → (1) and (2) (1) and (2) (1) and (2) (1) 28 days: n.d. brainstem Levels of 5-HTand metabolites Receptors5-HTT,5-HIAA/5-HT,L-TP, Levels 5-HTP of 5-HTlevels, and TPH activity 5-HT metabolites HTP L-TP, 5-HTP levels, TPH activity Receptors g 5-HTT 7 and 28 days: 5-HTT: hippocampus CA1 & g raphe

␮ ␮ , single n.d., s.c.), n.d. 5-HT: hippocampus (1) and (2) (1) and (2) (200 1 1 , i.p.), n.d. n.d. 5-HT: cortex − − ’ 1 − , s.c.), n.d. n.d. n.d. n.d. hypothalamus: 1 − 28 days hypothalamus gkg gkg

– ␮ ␮ gkg

g 100 g ␮

high dose ␮ T3 (s.c. implants 5-HIAA/5-HT: n.d. 5-HIAA/5-HT: spinal cord n.d. n.d. ‘ + + , p.o.), 7 and 28 days, p.o.), 7 n. dorsalis n. dorsalis cortex 1 1 7 days (2) frontal cortex − − – 2.5/5.0/7.5 mg), 7 days rostral (1) T4 replacement (15 15 days7 days s.c. injection) hypothalamus (1) frontal cortex (2) T4 kg 3 (2) T3 (100 kg b Rat (7) T4 (350 Rat (5) TXT Species/method Thyroid hormone treatment Brainstem/midbrain (raphe area) Whole brain, cortex, limbic system (outside raphe area) Rat (2) TXT Rat (3,4) (1) T3 (100 45 et Continued et et 47 et al a 50 62 58 Table 2 Author Tejani-Butt al Ramalho Upadhyaya & Rat (4) T4 (10 Agrawal al Sandrini al Henley

Molecular Psychiatry Thyroid serotonin relationship M Bauer et al

- 149 N , N ↓ )to ↑ frontal cortex density ; c 5-methoxy 2 = 2A 2A = normal levels after TXT restored ( 5HT prefrontal cortex 5-HT 5-hydroxytryptophan; = → ; T4 1A = hippocampus ↑ → → ) ↓ ↓↓ ↑↑ → ) ↓ → → → ↓↓ → subcutaneous; TCP monoamineoxidase inhibitor; 5-MeODMT = = 5-hydroxytryptamine (serotonin); 5-HTP challenge: = (3) frontal cortex 1A + TPH: frontal cortex hippocampus 5-HTT: hippocampus 5-HTT, 5-HIAA/5-HT, 5- 5-HT per os; s.c. = → L-tryptophan; MAOI 1A = not done. = : brainstem, substantia nigra, amygdala, entorhinal cortex. ↓ → 5-hydroxyindoleacetic acid; 5-HT = thyroidectomy. cant change; n.d. intraperitoneal; L-TP fi = (1) and (2) (1) and (2) (1) and (2) (1) and (2) (1) and (2): Levels of 5-HTand metabolites Receptors5-HTT,5-HIAA/5-HT,L-TP, Levels 5-HTP of 5-HTlevels, and TPH activity 5-HT metabolites HTP L-TP, 5-HTP levels, TPH activity Receptors = ) n.d. n.d. n.d. n.d. 5HT d g 5-HTT & TPH: midbrain ), hippocampus ␮ 1 no signi − = 8-hydroxy-2-(di-n-propylamino)tetralin; p.o. T3 (100 5-HT , single From (5) and (6) n.d., s.c.), 5-HT:, s.c.), n.d. hippocampus n.d. hippocampus ( gkg 1 1 1 → − − − = + ␮ agonist 1A gkg gkg gkg

␮ ␮ ␮ agonist (8-OH- hippocampus 5-HT 1A + , s.c.), 7 days (5) frontal cortex 1 desmethylimipramine; 5-HIAA − + = , s.c.), 4 wks, s.c.), 4 wks ), 21 days midbrain (2) cant decrease; 1 1 1 − − − fi gkg (5) 5-HT (1) T4 replacement (15 7 days(4) Clomipramine (10 mgkg 7 days hippocampus (4) frontal cortex ␮ Desipramine and T3 (dose (3) T3 (100 21 days DPAT)(6) T3 (100 (6) frontal cortex ( (8-OH-DPAT) s.c. injection)(2) Clomipramine (10 mgkg evidence for indirect (1) frontal cortex (2) T4 high (200 kg tryptophan hydroxylase; TXT : DMI = signi nucleus; 8-OH-DPAT = b ↓ = d Species/method Thyroid hormone treatment Brainstem/midbrain (raphe area) Whole brain, cortex, limbic system (outside raphe area) Rat (7) (1) T3 (100 Rat (3) TXT Rat 51 Continued 61d cant increase; 5-hydroxytryptamine (serotonin) transporter; i.p. 59 et al fi : neocortex, basal ganglia, olfacto-limbic areas, spinal cord; 5-HT = a 2A ; TPH et al signi = = Only abstract available. For methods: see Table 1. In order of the year published. 5-HT T3 Table 2 Author Gur a b c d ↑ Non-Standard Abbreviations 5-HTT Watanabe dimethyltryptamine; n. Kulikov

Molecular Psychiatry Thyroid serotonin relationship M Bauer et al 150 on 5-HT receptors.50–52 The effects on the serotonergic the activity of the metabolizing enzyme monoamine system were more pronounced with higher doses of oxidase (MAO) before and after treatment in 45 hyper- thyroid hormone in two out of three studies.50,52 thyroid patients and compared the activity to that 52 Cortical and hippocampal 5-HT2 receptors. and hip- present in healthy, euthyroid controls. Serotonin pocampal and hypothalamic (postsynaptic) 5-HT1A levels were found to be increased, and MAO activity receptor density50 were significantly increased after decreased, in the hyperthyroid state68 (Table 3). After

administration of higher doses of T3 or T4. However, 3 months of treatment with carbimazole and the asso- excess serum thyroid hormone in thyroidectomized ciated decline of plasma T3 and T4 concentrations rats, achieved by administration of high doses of T4, towards normal levels, MAO activity increased and did not produce any changes in cortical 5-HT2A recep- plasma serotonin concentrations decreased, however, tors when compared to thyroidectomized animals with not to within the range of the normal control subjects.68 normalized thyroid hormone levels.51 These findings suggest altered serotonin metabolism In summary, 5-HT receptor studies in adult euthy- during the hyperthyroid state. roid rodents indicate that thyroid hormone application

may desensitize presynaptic 5-HT1A raphe autorecep- Serotonin-HPT system interaction in patients with tors, and thus increase cortical serotonin release, an major depression The interaction of the 5-HT system effect similar to that described after addition of the 5- and thyroid axis function was investigated in patients

HT1A to an ongoing SSRI with major depression using the D-FEN stimulation treatment.63 The receptor studies also indicate that thy- test69 (Table 3). Patients with HPT system abnormali-

roid hormone application may increase cortical 5-HT2 ties (as indicated by a blunted TSH response to the receptor sensitivity. This increase in 5-HT2 receptor TRH stimulation test suggesting ‘hyperactivity’ of the function does not seem to be linear, as stress-induced HPT system) had hormonal D-FEN responses compara-

activation of hypothalamic 5-HT2 receptors was ble to those of healthy controls, while patients without 62 blunted in hyperthyroid rats. Cortical 5-HT2 receptor HPT abnormalities showed reduced hormonal densities were only increased after prolonged treat- responses to D-FEN compared to controls. The authors ment with relatively high doses of thyroid hormone in suggested that the blunted TSH response to TRH stimu-

thyroidectomized rats. In contrast, standard doses of T3 lation found in a subgroup of depressed patients might in euthyroid rats resulted in a decrease in the number be a compensatory mechanism for diminished central 69 of cortical 5-HT2 receptors. 5-HT activity. Clinical studies of the thyroid–serotonin interaction Implications for thyroid hormone modulation of The serotonin system in hypothyroid patients and mood disorder effects of thyroid hormone replacement In three studies, parameters of the serotonergic system were Does the information reviewed here of the interaction examined in hypothyroid patients (Table 3). Sjo¨berg et of thyroid hormones with serotonergic neurotransmis- al64 measured 5-HT, L-TP and 5-HIAA concentrations sion, have relevance for our understanding of the mood in the CSF of seven hypothyroid patients before and modulating effects of thyroid hormones in the clinical setting, and can it promote our understanding of the after T4 replacement. A significant decrease in the sero- pathophysiology and treatment of mood disorders? tonin precursor L-TP after T4 treatment was found which may indicate increased conversion to 5-HT. The molecular mechanisms underlying the efficacy However, no significant increase in CSF 5-HT or 5- of thyroid hormone treatment in patients with mood disorders, and in patients with primary hypothyroid- HIAA concentrations after T4 replacement was found. Several studies in an effort to evaluate functional ism who have comorbid depression, are not known. components of the serotonergic system in humans have From the few studies in humans with thyroid dysfunc- examined the neuroendocrine responses to d-fenflur- tion, there is some evidence from the neuroendocrine amine (D-FEN). D-fenfluramine stimulates the sero- challenge studies that hypothyroid status is associated tonergic projecting pathways from the dorsal raphe with a reduced 5-HT responsiveness. Furthermore, this nuclei to the paraventricular nucleus of the central appears to be reversible with thyroid replacement ther- 65,67 hypothalamus and seems to release via acti- apy. However, given the small number of studies 65,66 in humans definitive conclusions cannot be drawn. Not vation of 5-HT1A or 5-HT2 receptors. Two such challenge studies found a significantly decreased D- only is the number of studies limited but the sample FEN-induced cortisol response in hypothyroid sizes in the studies were small and the methods 65,67 employed to assess central 5-HT function varied con- patients (Table 3), which normalized with T4 replacement.67 This enhancement of central 5-HT siderably. It is also questionable whether the periph- 2 eral blood and CSF content of 5-HT and its metabolites receptor activity after T4 application in previously hypothyroid patients67 is in agreement with the find- provide an index of brain serotonergic neurotransmis- sion,70 while neuroendocrine challenge studies pro- ings in animal studies of increased 5-HT2 receptor sen- 54,60 vide only an indirect way of ‘probing’ central 5-HT sitivity after T3 application. function.71 The serotonin system in hyperthyroid patients One In contrast, results from studies in animals provide study examined peripheral 5-HT concentrations and strong evidence that thyroid status has a considerable

Molecular Psychiatry Thyroid serotonin relationship M Bauer et al 151 reduced = metabolism related to function and CSF biogenic amines ; metabolism in ↑ cant hypothyroidism ↓ fi among HPT dysregulation may hypothalamic-pituitary-thyroid axis; 5-HT ↓ ), MAO controls ↑ = , MAO ↑ vs thyrotropin. = ↓ controls: altered biogenic amine vs → post-treatment: interaction between thyroid cant enhanced cortisol reduced 5-HT → fi vs HT and thyroid hormoneno levels; sex difference 5-HIAA normal in patients withd-FEN reduced response receptors 5-hydroxyindoleacetic acid; HPT = thyrotropin-releasing hormone; TSH = blood: 5-HT levels and MAOtreatment patients with carbimazole (3months) post-treatment 5-HT ( d-FEN test: cortisol and hypothyroid patients: signi positive correlation between 5-T4 replacement thyrotoxicosis d-FEN test (see above) & TSH TSH response to TRH 5-HT uramine; 5-HIAA fl d-fen vs vs = cant change. vs fi levothyroxine; TRH = serotonin interaction no sign (female/male) 45 (25/20) 20 (11/9) response to TRH stimulation patients with normal d-FEN compensate for reduced – uid; d-FEN = fl → vs vs healthy, stimulation (centrally acting response cerebrospinal vs = cant decrease; monoamineoxidase; T4 fi = : CSF signi = ↓ SubjectsHyperthyroid patients healthy, euthyroid controls 46 (25/21) Sample sizeHypothyroid n patients (four activityof before 10 and with after majordepression) 10 (8/2) Test procedure/treatmenteuthyroid controlsHypothyroid patients (two pre-treatmentof Results 5-HT seven with majordepression), no 7 controls (6/1)Hypothyroid 10 patients, (8/2) no 9 (7/2)Euthyroid patients with d-FEN testmajor before depression prolactin and response after tohealthy, d-FEN euthyroid controls 60 (33/27) reduced signi both CSF cortisol levels and of 5-HT tryptophan, releasing 5- agent) Conclusions by authors pre- T4 replacement central 5-HT activity test response post-T4 treatment responsiveness reversible (euthyroid status) response; TSH response to TRH sensitivity of with 5-HT T4 replacement controls HT, 5-HIAA before and after tryptophan 68 64 et al 65 67 69 Clinical studies in humans on the thyroid cant increase; fi et al et al et al a et al signi berg ¨ 5-hydroxytryptamine; MAO = In order of the year published. ↑ Non-Standard abbreviations = Table 3 Author Upadhyaya a Cleare Cleare Sjo Duval

Molecular Psychiatry Thyroid serotonin relationship M Bauer et al 152 impact in serotonergic neurotransmission in the adult serotonergic neurotransmission via two independent

brain. Experimentally-induced hypothyroid states mechanisms: (1) by reducing the sensitivity of 5-HT1A result in an increase in 5-HT turnover in the brainstem. autoreceptors in the raphe area, thus disinhibiting Increased 5-HT turnover in hypothyroid states may cortical and hippocampal serotonin release; and (2) by

lead to an increase in raphe 5-HT1A autoreceptor increasing cortical 5-HT2 receptor sensitivity, a poten- activity and a decrease in cortical 5-HT concentrations tially independent way of increasing 5-HT neuro- (Figure 1). This observation indicates that in the raphe transmission (Figure 1). These latter two potential area increased serotonin turnover may activate inhibi- mechanisms for thyroid hormone modulation of sero- tory autoreceptors on the serotonergic cell bodies and tonin transmission warrant further elaboration. With thus, reduce serotonin turnover in the cortical and sub- respect to the first mechanism, it is important to note cortical projection areas of these serotonergic neurons. that in animal studies it has been demonstrated that The value of direct measurements of 5-HT and its an acute blockade of serotonin transporters by SSRIs precursors/metabolites from homogenized brain increases raphe serotonin concentrations immedi- tissues is limited. However, in more recent receptor ately.72,73 However, application of SSRIs also activates

studies, it was found that hypothyroid states result in presynaptic 5-HT1A autoreceptors located on sero- a decrease in cortical 5-HT2A receptor density, an tonergic cell bodies in the raphe area and may thus observation that reinforces the postulate that hypothy- inhibit serotonin release in the cortical projection roidism is associated with a reduced cortical sero- areas.23 Subsequently, an increase in frontal serotonin tonergic neurotransmission. release is only found after prolonged SSRI appli- Thyroid hormone application may increase cortical cation,74 when increased synaptic serotonin concen- trations in the brainstem induce a down-regulation of

5-HT1A autoreceptors, or after a -induced blockade 75 of 5-HT1A receptors. This mechanism has been postu- lated 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 thy- roid 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,77–80 although not all studies of patients with major depression.81 Subsequently, treat-

ment 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 hypoth-

esis of 5-HT2 receptor-mediated antidepressive effects of thyroid hormones faces some limitations. First, the serotonin receptor subtypes perturbed in the neuroen- docrine 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).82–85 The observed effect Figure 1 The thyroid–brain serotonin system interrelation- might be mediated via various contributions of both 5- 66,86,87 ship in adult animals. (a) Experimentally-induced hypothy- HT2C and 5-HT1A receptor stimulation. Second, roidism. (b) Effects of thyroid hormone on the brain sero- autoradiographic and brain imaging studies, measuring tonin system. not the sensitivity but the density of 5-HT2 receptors

Molecular Psychiatry Thyroid serotonin relationship M Bauer et al 153 among patients with major depression, observed sig- behavioral or neuroanatomical abnormalities com- nificant decreases in frontocortical 5-HT2 receptor pared with animals rendered hypothyroid by thyroid- availability after antidepressive drug treatment.88,89 Of ectomy95–98 suggesting that other TR forms may com- course, increases in receptor sensitivity may be pensate or substitute for lacking or defective receptors accompanied by decreases in receptor number to avoid in these knock-out mouse models. In contrast, a TR overstimulation of the monoamine neurotransmitter knock-in mouse model with a T3 binding mutation in system and this may be the explanation. Such a the TR␤ locus resulted in severe neuroanatomical and hypothesis would be supported by the observation in behavioral dysfunction (eg, abnormal hippocampal animal studies of Heal and Smith,54 Sandrini et al58 gene expression of brain-derived neurotrophic factor 61 and Watanabe that cortical 5-HT2 receptor density (BDNF), myelin basic (MBP), and pro- was reduced after thyroid hormone application, a pro- tein kinase receptor B (TrkB), learning deficiency, and cedure which has been shown to increase the sensi- cerebellar dysfunction) indicating a specific and del- tivity of this receptor subtype.54,60,65,67 eterious 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 Further considerations thyroid hormones.100 Among the most extensively Post-receptor and molecular actions of thyroid studied loci is RT3/neurogranin, a brain-specific gene hormones encoding a protein kinase C substrate that binds calmo- While not the primary focus of this review, other sites dulin and is located in dendritic spines and forebrain of thyroid hormone action that are important for under- neurons;101 in these studies, adult-onset hypothyroid- standing thyroid hormone effects on brain function, ism led to a decrease of RC3/neurogranin, an effect that 102 include post-receptor, transcriptional, and gene regu- was reversible with T4 treatment. Thyroid hormone latory mechanisms. A series of studies indicate that also modulates transport processes across the these signaling pathways, downstream from receptors, blood–brain barrier (BBB)103 and in astrocytes,104 and are also influenced by changes in thyroid status. In rats, may alter the expression of glucose transporter one hypothyroidism induced a significant up-regulation of (GLUT-1) gene, the principal isoform responsible for G-protein complexes in synaptosomal membranes from glucose transport across the BBB.105 Furthermore, the different brain regions.90 Conversely, in studies of effects of thyroid hormones on CNS gene expression euthyroid animals, treatment with T3 decreased the have been demonstrated for various other neuroactive 106 abundance of the alpha-subunits of Gi in synaptosomal , eg, TRH, corticotropin-releasing hormone membranes of the cerebral cortex.91 Impaired signal (CRH),107 brain-derived neurotrophic factor, nerve transduction via adenylate cyclase and inositol phos- growth factor and neurotrophin 3,108,109 angiotensin- phatase has also been demonstrated in the adult brain ogen,110 and several structural brain-specific genes (eg, of hypothyroid rats. Hypothyroid rats also showed myelin-associated glycoprotein, Pcp-2, microtubule- enhanced inhibition of adenylate cyclase in synaptoso- associated ).111 Of particular relevance is a mal membranes by GTP,92 and decreased formation of recently reported interaction between thyroid and sero- inositol phosphate in response to the muscarinic chol- tonin systems, indicating synergistic effects of T3 and 93 inergic agonist carbachol. Thus, it appears that thy- 5-HT1A receptors on hippocampal brain-derived neuro- roid hormones exert an important influence on the trophic factor (BDNF) expression. T3 administration activity and synthesis of G-proteins and the receptor/G- prior to treatment with a 5-HT1A agonist caused a coupling systems that serve the monoamine receptor downregulation of hippocampal BDNF mRNA system. Thus thyroid hormone deficiency leads to an expression in adult rats.111 These molecular studies impairment in adenylate cyclase activity and phospho- clearly indicate that thyroid hormones actively regu- inositide-based signaling pathways involved in tran- late a broad spectrum of genes in the adult brain scriptional activities in the adult CNS.16,90,91 although the behavioral significance of such activity The molecular action of thyroid hormone is is unknown. mediated through specific nuclear TH receptors (TRs) ␣ and ␤ (␤1, ␤2), functioning as ligand-dependent tran- Conclusions scription factors that increase or decrease the expression of target genes.94 Although the two genes In our review we found evidence, particularly from that encode the related TR␣ and TR␤ are differentially results in animal studies, to support the hypothesis expressed, the two receptors usually coexist in the that thyroid status impacts the serotonin system in the same cell type. The relative contribution of these two adult brain, and that increasing thyroid hormone levels TR genes encoding for TR␣ and TR␤ in mediating a increase serotonin neurotransmission. Given the particular T3 response is poorly understood because of important role of the serotonin system in the pathogen- a lack of in vivo functional information. Knock-out esis of depression we speculate that the serotonin sys- mouse models lacking a particular TR isoform have tem may be involved in the mood modulating effects been generated to explore the relative contribution of of thyroid hormones among patients with affective dis- each of the TR isoforms to the TH-mediated regulation orders. This hypothesis would explain why thyroid of various biological processes in different tissues. hormones are most effective in patients with affective However, the animals tested to date showed little overt disorders when administered as an adjunctive treat-

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