‘a are comin Sere Thyroid hormones, serotonin and mood: of synergy and significance in the adult brain M Bauer’, A Heinz®, and PC Whybrow! ‘University of Califomia Los Angeles (UCLA), Neuropsychiatric Institute & Hospital, Department of Psychiatry and Biobehavioral Sciences, 760 Westwood Plaza, Los Angeles, CA 90024, USA; *Central Institute of Mental Health, Department of Addictive Behavior and Addiction Research, 68159 Mannheim, Germany ‘The use of thyroid hormones as an effect 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 con- sistently reported while decreased cortical 5-HT concentrations and §-HT,, receptor density are less frequently observed. In the majority of studies, the effects of thyroid hormone admin- istration in animals with experimentally-induced hypothyroid states include an increase in cortical 5-HT concentrations and a desensitization of autoinhibitory 5-HT,, receptors in the raphe area, resulting in disinhibition of cortical and hippocampal 5-HT release. Furthermor there is some indication that thyroid hormones may increase cortical 5-HT, receptor sensi tivity. In conclusion, there is robust evidence, particularly from animal studies, that the thyt ‘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-HT,, autoreceptors in the raphe area, and by increasing 5-HT, receptor sensitivity. ‘Molecular Psychiatry (2002) 7, 140-156. DOI: 10.1038/sjmp/4000963 Keywords: thyroid system; T,; Ts; serotonin system; adult brain; §-HT receptor; mood modulation; affective disorders; depression Introduction The thyroid system and mood modulation in affective illnes Disorders of the thyroid gland are frequently associated with severe mental disturbances.'* This intimate association between the thyroid system and behavior has been the impetus for exploring the effects of thy- roid hormones in modulating affective illness, and the role of the hypothalamic-pituitary thyroid (HPT) axis in the pathophysiology of mood disorders.’ Thyroid hormones (TH) have a profound influence on behavior and mood, and appear to be capablo of modulating the phenotypic expression of major affective illness." Correspondance: M Bauer, MD, PhD, Department of Psychiatry and Biobehavioral Sciences, University af California Los Angeles (UCLA), 300 Medical Plaza, Suite 2390, Los Angeles, CA 90005, USA. E'mall: mjoauerd@mednet.uela.edu Received 14 March 2001; revised 7 June 2001; accepted 15 June 2001 Thyroid supplementation is now widely accepted as an effective treatment option for patients with affective disorders." Actions of thyroid hormones in the adult brain It is well ostablished that thyroid hormones are essen- tial for both the development and maturation of the human brain, affecting such diverse events as neuronal, processing and intogration, glial cell proliferation, myelination, and the synthesis of key enzymes required for neurotransmitter synthesis."°** Thyroid deficiency during the perinatal period results in irre- versible brain damage and mental retardation. How- ever, despite this accepted body of knowledge and in, disregard of the clinical and therapeutic observations in association with affective illness, the action of thy- roid hormones in CNS function in adults has not been widely acknowledged by general endocrinologists. ‘This lack of interest sooms to have originated in the 1950s and 1960s, when early physiological studies sug-gested that oxygen consumption in the mature human brain did not change with changing thyroid status."*"* 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." However, with improved methods in basic research the action of thyroid hor- mones in the mature brain has become a subject of greater interest."® There are several lines of evidence suggesting that thyroid hormones affect mature brain function. First, thyroid hormone receptors are preva- lent in the mature brain. Nuclear receptors for T;, the thyroid hormone with the highest biological activity, are widely distributed in adult rat brain with higher densities of nuclear T, receptors in phylogenetically younger brain regions—in the amygdala and hippo- ‘campus—and lower densities in the brain stem and cerebellum." A second line of evidence pertains to brain thyroid hormone metabolism. The process of 5- deiodination by which both thyroid hormones, T, and ‘Ty, 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 spe- cific cell types." D2 is expressed primarily in the brain and anterior pituitary gland where it metabolizes T, to the active thyroid hormone form, T;. The activity of D2 in distinct regions of the brain varies widely, with the highest levels found in cortical areas and lesser act in the midbrain, pons, hypothalamus and brainstem.°” In rat brain D2 is expressed in neurons, in particular in the nerve terminals, but also in astrocytes." Third, thyroid hormones have been detected in relatively high (nanomolar) concentrations in cortical tissue. In con- trast to peripheral tissue where T, concentrations usu- ally far exceed those of T;, in the brain T, and T con- centrations are in an equimolar range. Monoamines and mood Over the past two decades it has become apparent that the monoamines, specifically norepinephrine and sero- tonin play a major Tole in mood modulation.” 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 inter- dopendence of these long tracks—including the dopa- mine system—with thyroid hormone metabolism has become better understood as our technology has improved. ‘The eotocholamilnerglo ayatain was hultally invadt- gated largely because of the known physiological association between sympathetic activity and thyroid hormones.** Thyroid hormones appear to play an important role in regulating central noradrenergic (NA) function and it has boon suggested that thyroid dys~ function may be linked with abnormalities in central NA neurotransmission.*” Evidence for a thyroid-NA. “Thyroid serotonin relationship Ber ea interaction derives largely from immunohistochemical mapping studies demonstrating that T, is concentrated in both nuclei and projection sites of central NA sys- tems. Recent evidence that T; is also delivered from the locus coeruleus to its NA targets via anterograde axonal transport indicates that T; may function a cotransmitter with norepinephrine in the adrenergic nervous system.” However, the neuropharmacological offects and functional pathways underlying the therapeutic effects of thyroid hormones in patients with affective dis- orders are still unclear. One of the most intuitive hypotheses postulates the existence of a brain thyroid hormone deficiency in affective illness. Thyroid hor- mone therapy can then be considered a replacement therapy with a possible mechanism of action being its pharmacological effects on monoamine —neuro- transmitter systems, eg, by increasing p-adrenergic receptor activity and thus promoting the action of cat- echolamines at central receptor sites.” The GNS serotonin system As with the noradrenergic and dopaminergic systems, the bulk of the CNS serotonergic nerve terminals orig- {nate in the neuronal cell bodies of the brainstem raphe nuclei and project, both rostrally and caudally, to neu- roanatomically discrete areas throughout the brain but with extensive innervation of the cerebral cortex and the limbic system.” Although the serotonin system has been given prominence in recent deliberation regard- ing mood modulation, particularly since the advent of drugs that specifically interfere with serotonin neu- ronal reuptake systems, there has been little investi- gation of the relationship of this system to the thyroid system. This paper analyzes the existing literature per~ taining 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 tho past threo decades has yielded compelling evidence that the serotonergic system is intimately involved in the pathogenesis of depression.****"% Changes in serotonergic neuro- transmission have been repeatedly associated with the therapeutic response to antidepressant and mood stabi- lizing medication.*** Almost all currently employed treatments for depression, including the tri depressants, the SSRIs, the MAO inhibitors, and ECT, directly or indirectly augment serotonergic neurotransmission."* 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-responsivo depression.***° 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 unmedi- cated depressed patients.” In brain imaging studies, clinical depression was associated with reduced sero- tonin transporter availability.**” 1a ‘Molecular Psychiatry12 ‘Thyroid serotonin relationship Bae eta 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 sero- tonin system, specifically by enhancing cortical sero- tonergic 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 lim- bic 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 yoars that are the subject of our review Specifically, many early studies were based upon crude analyses of levels of serotonin and its metab- olites in homogenized brain tissue of animals that had been previously exposed to hypo- or hyperthyroid states. As technology advanced and our chemical dis- section 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 stud- ies of transporter systems began to complement the earlier studies, and most recently, microdialysis tech- niques have provided new insights by measuring levels of serotonin in vivo. We have tried to reflect this tochni- cal advance in the analysis of the papers that are reviewed. ‘Methods of literature research An attempt was made to identify all reports study 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’, ‘sero tonin’, ‘brain’ and ‘affective disorders’ was performed, supplemented by the bibliographies of reports ident- ified. Results of the review Effects of experimentally-induced hypothyroid states on brain serotonin system in animals Historical perspective: studies in neonatal animals Sti- mulated 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 (S-HT, serotonin) and 5-HIAA, the main 5-HT metab- olite, were found to be significantly elevated and the serotonin precursor 5-hydroxytryptophan (5-HTP) to be decreased compared to euthyroid controls indicat- ing an increased serotonin turnover rate in the neonatal period.%* Other data have demonstrated that neonatal Molecular Psychiatry hyperthyroidism induced by daily application of T, also resulted in an increased turnover of 5-HT."* Measurements of 5-HT and its metabolites in adult hypothyroid animals In the adult rat brain, hypothy- roidism generally induced lesser changes in the sero- tonergic system compared to the studies in neonatal animals. Thirteen studies were identified that meas- ured the effects of experimentally-induced hypothy- roidism 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 euthy- roid animals.” Later, using more sensitive assay tech- niques, five studies measured 5-HT and 5-HIAA con- centration or the 5-HIAA/S-HT ratio as an indicator of the serotonin turnover and reported increased 5-HT ‘metabolites in the brainstem**~* (notice: one study cal- culated the inverse ratio, 5-HT/5-HIAA"). Reduced 5- HT concentrations in the cortex,**” and reduced con- centrations of the serotonin precursor 5-HTP_ were reported in the whole brain** of hypothyroid adult rats. ‘These findings of increased 5-HT turnover in the brain- stem 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-HT,, autoreceptors and sub- sequently decrease serotonin release in the cortical projection areas. Receptor studies: changes in 5-HT,, and 5-HT, recep- tors in the adult hypothyroid brain’ Among the many 5-HT receptor subtypes with different regional distri- butions throughout the CNS, it is the 5-HT,, and 5- HT, receptor densities that have been most studied in experimentally-induced hypothyroid animals. The 5- HT, 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-HT, receptors located in distinct projec- tion areas of the 5-HT neurons. In experimentally-induced hypothyroid states the 5- HT, (presynaptic) receptor density in the brainstem and midbrain was not altered**-* (Table 1). Studies on the density of 5-HT,, (postsynaptic) receptors outside the brainstem yielded contradictory results, An increase in cortical and hippocampal 5-HT,, (postsynaptic) receptors was observed by Tejani-Butt et aP® but not by Hong et al and Kulikov et al" who found no significant differences compared to euthyroid adult rodents, An early study by Mason et af found a decrease in 5-HT, receptor density in the striatum but not in the cortex of hypothyroid adult rats. However, when 5- HT, receptors were assessed selectively in severely hypothyroid rats, a significant cortical reduction was recently reported by Kulikov et al.** Hence in summary, several lines of evidence indicate that an experimentally-induced hypothyroid state ine 18 (panunuoo) = une “seoqeoday “snduseaodd “xano3 pu worse Sy znd (6) yo 10 OH 1 p09 yeu 14 Su 2 "Veo + LXE. (© ps0o feuds ‘pu suiesyvvir® (@ pur (1) pu Sym 2ALXL() (2) : i pa pu pu LIrS/vvIne SNE UXL (IML lO 1 AoquoHL Fumes 5 = xan ‘pu pu pu ‘pu shop Se-12 UXL (6) 1 a 70 woseyy é 1 ojpung urexqouoy pexpout : nyu H wrt ayes EY 1 snunypat ylocud Toutes eu, seg soquyt ues vu pu nts VWIES/LHS ‘pu vynrsare Shep 21d (2) Al 9 prbang woyeqdeatorpoeou pu pu pu sm cux, (ant pu vu pu Sm FKL (IL INMNS vu pu eu Shep 52 “UxL (0) O29 S G00 Anono0 Ha, 100 LHL vues Suns “sunrsivvnes “bits “urs somoquio Sonjoqoqou pu ssojdacoy puo sure fo-sjaany —stoydao0y 18-8 fo sana (oni exo aprsino) wraps argu xapoo “uuy apoy, (bOI etydau) urONapHU ma ony waysks uTUO}OIOS UIEIG UO sayeIs ploxyody psonpur-AyperuoWEEAXE Jo SHOOT T AqEL, Molecular Psychiatry-d = apa ‘01 “kxouphtys = ‘OnlaHy/StsA[orporores = ¢ (yA) Kos (Aydex#oyeurosy> pnby aoueunojiad- oxo osuodsos yesoiasyg = ¢ “Boypuny TMH = Z “Anowouony(-onsods)/sydesSoyeuros4 pymbyy = L power 9pi0 uh, 1 xawoo rey = sndunsody tL Ho andumoddy — —endumesoddiy “urs —ayeqpru (Oey ow Aon {pros pads vu pe LPS/VVUHS 46) 0 (1) pu aw Koquoy, wnsuyeiq urs = uy i vvI mea 3 " pu) pur (2) (vy ¥ioquay, i = mduwaoday = yds ‘snuunpeqiodsiy xay309 = oydax we i Lins stjetop “a 2 amgeralag i 1 some iy pu pu Tsouoo Ke pu ped, Suns Vanes Vue sonoqenaur pun sioidesony pun ue Jo sje] —suoydeonyy pts Jo s]8407 Pe Jsapradg atoyiny: (oan aydou eprsjno} woysis quay xau09 “urowg aJoym — (oar aydo1) urDAKy Panunwoy 1 ayqey, Molecular Psychiatryadult rodents is associated with an increased 5-HT turnover rate in the brainstem, but not with a change in 5-HT,q 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-HT, 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 (T, and/or T,) 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). Acute effects of thyroid hormones on levels of 5-HT and its’ metabolites in the brainstem and mid- brain Rastogi and Singhal” observed an increase in, the 5-HT precursor L-tryptophan (L-TP), and Heal and ‘Smith® found an increase in both 5-H and 5-HIAA in the midbrain after T, application in euthyroid animals. In contrast, Henley et al‘? examined animals after thyroidectomy, which resulted in an elevated sero- tonin turnover rato; in these animals, T, 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, T; replacement for longer than 3.5 days reduced the 5-HT turnover in cau- dal brainstem to completely normal values. The ctivity of tryptophan hydroxylase (TPH), the rate-lim- iting enzyme in the synthesis of 5-HT, was found unaltered in the midbrain after T, application.*** 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 meas- ured 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."""-*"4*™ These results indicating increased cortical 5-HT_tumover 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." 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 T, or T, application on cortical serotonergic neuro- transmission in euthyroid rodents**8* (Table 2). In three of four studies, increases in cortical or whole brain 5-H'T, 5-HTP and 5-HIAA contents were observed. only after repeated (chronic) thyroid hormone appli- cation.2135 ‘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 ‘Thyroid serotonin relationship Wo eta pronounced after repeated (chronic) thyroid hormone application. Similar studies investigating the effects on 5-HT levels in the brainstem and midbrain are less con- sistent (Table 2), Effects of thyroid hormones on 5-HT,. receptor density and sensitivity Throo autoradiographic studies have reported that thyroid hormone application induces no significant reduction in raphe and midbrain 5-HT,, receptor density.**-* However, a recent study by Gur et a indicated a loss of autoinhibitory 5-HT,, receptor sensitivity mediated by T, (Table 2). Gur et al,*° 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 sero- tonin release that follows the application of a 5-HT,, agonist via the activation of inhibitory autoreceptors was significantly reduced by T; alone, or T; combined with clomipramine administration in euthyroid rats." Effects of thyroid hormones on 5-HT, receptor density and sensitivity The database concerning changes in 5- HT, receptor density after thyroid hormone application reveals contradictions. Mason et al observed an increase in 5-HT, receptor density in the striatum, hip- pocampus and cortex of thyroidectomized rats only after long-term application of a relatively high dose of either , (250-1000 yg kg" for 7-10 days) or T, (250- 500 yg kg" for 710 days). Kulikov et al" showed that ‘T, application in thyroidectomized animals returned cortical 5-HT2, receptor densities to normal levels, inrespective of whether a replacoment or high T, dose was applied (15 yg kg" vs 200 ug kg" T, for 21 days each). Lower doses and shorter duration of T, appli- cation yielded different results: Sandrini et af** found no significant effect on 5-HT, receptor density in the hippocampus and a decrease in cortical 5-H, receptor density after application of T, in euthyroid rats (100 ug kg for 3-7 days). In the study of Heal and Smith the same T, dose applied to euthyroid rats (100 wg kg for 10 days) also decreased cortical 5-HT, receptor density. A reduction in prefrontal 5-H, receptors was observed after coadministration of T, and the antidepressant desipramine.** A thyroid hormone-induced change in receptor sen- sitivity was observed for cortical 5-HT, receptor func- tion in adult outhyroid rats. Heal and Smith'* observed an increase in 5-HT, receptor sensitivity after short- term T application, and Atterwill” reported similar findings after both short- and long-term T., application (Table 2). Under stress conditions, on the other hand, administration of high doses of T, (950 wg kg” for 7 days) resulted in a blunting of the immobilization stress-induced activation of hypothalamic 5-H: recep- tors. 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 45 Molecular Psychiatry(pon 00) Baer eta ‘Thyroid serotonin relationship pe pu Lure ogo SLs { anexq 9 : pu ‘pu ston skep pL “8 oot Hr 0s) BL (2) A 1D 19 prwang. + dou. 40 auyzedinb) staat Lars + sxep OF +1 Sf ou) e (8) (uaooN-s 40 pu pu step oF = 7 woqu pu ‘nf? 19 OL ‘upeaqpnt He. pw | urmqprar a7 P pu qoo0 el? pu . 2 wonséug LHS vues “ure saqjoqunua sioyda00y uo ..1-¢ fo sjasxy ea pe fo sao ssojda0oy epououtr auowoy proiy, —jsaqoadg (oan oydos) ummigprajaraisuraig uuysés uuojoz0s uyesq UO uoRwYdde ouONOY PIOLAYA Jo SHAE z oqEL Molecular Psychiatrye a (panuyu0p) — wyeaq 9104 ELS | ueaq atoqs “vines pu pu Shep gos 818M sz) ek (ZI fo 19 FINAN = woysureg (o) A yeu? 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However, excess serum thyroid hormone in thyroidectomized rats, achieved by administration of high doses of T, did not produce any changes in cortical 5-H, recep- tors when compared to thyroidectomized animals with normalized thyroid hormone levels.** In summary, 5-HT receptor studies in adult euthy- roid rodents indicate that thyroid hormone application, may desensitize presynaptic 5-H, raphe autorecep- tors, and thus increase cortical serotonin release, an cffect similar to that described alter addition of the HT,, receptor antagonist pindolol to an ongoing SSRI treatment." The receptor studies also indicate that thy- roid hormone application may increase cortical 5-HT receptor sensitivity. This increase in 5-HT, receptor function dovs not seem to be linear, as stress-induced activation of hypothalamic 5-HT, receptors was blunted in hyperthyroid rats."* Cortical 5-HT, receptor densities were only increased after prolonged troat- ment with relatively high doses of thyroid hormone in thyroldectomized rats. In contrast, standard doses of T, in euthyroid rats resulted in a decrease in the number of cortical 5-HT, 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). Sjoberg et al measured 5-HT, L-TP and 5-HIAA concentrations in the CSF of seven hypothyroid patients before and after T, replacement. A significant decrease in the sero- tonin precursor L-TP after T, treatment was found which may indicate increased conversion to 5-HT. However, no significant increase in CSF 5-HT or 5- HIAA concentrations after T, replacement was found. Several studies in an effort to evaluate functional components of the serotonergic system in humans have examined the neuroendocrine responses to d-fenflur- amine (D-FEN). D-fenfluramine stimulates the sero- tonergic projecting pathways from the dorsal raphe nuclei to the paraventricular nucleus of the central hypothalamus and seems to release cortisol via acti vation of 5-HT,, or 5-HT, receptors.""* Two such challenge studies found a significantly decreased D- FEN-induced cortisol response in hypothyroid patients” (Table 3), which normalized with T, replacement.” This enhancement of central 5-HT, receptor activity after T, application in_ previously hypothyroid patients” is in agreement with the find- ings in animal studies of increased 5-HT, receptor sen- sitivity after T; application." The serotonin system in hyperthyroid patients One study examined peripheral 5-HT concentrations and Molecular Psychiatry the activity of the metabolizing enzyme monoamine oxidase (MAO) before and after treatment in 45 hyper- thyroid 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 state (Table 3). After 3 months of treatment with carbimazole and the asso- ciated decline of plasma T, and T, concentrations towards normal levels, MAO activity increased and plasma serotonin concentrations decreased, however, not to within the range of the normal control subjects." These findings suggest altered serotonin metabolism during the hyperthyroid state. Serotonin-HPT system interaction in patients with major depression ‘Tho interaction of the 5-HT system, nd thyroid axis function was investigated in patients, with major depression using the D-FEN stimulation test® (Table 3). Patients with HPT system abnormali- tios (as indicated by a blunted TSH response to the ‘TRH stimulation test suggesting ‘hyperactivity’ of the HPT system) had hormonal D-FEN responses compara- ble 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 stimu- lation found in a subgroup of depressed patients might bbe a compensatory mechanism for diminished central S-HT activity." Implications for thyroid hormone modulation of mood disorder Does the information reviewed here of the interaction of thyroid hormones with serotonergic neurotransmis- sion, have relevance for our understanding of the mood modulating effects of thyroid hormones in the clinical ing, and can it promote our understanding of the pathophysiology and treatment of mood disorders? ‘The molecular mechanisms underlying the efficacy of thyroid hormone treatmont in patients with mood disorders, and in patients with primary hypothyroid- ism who have comorbid depression, are not known, From the few studies in humans with thyroid dysfunc- tion, 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 ther- apy.'®*” 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 con- siderably. It is also questionable whether the periph- eral blood and CSF content of 5-HT and its metabolites provide an index of brain serotonergic neurotransmis- sion,” while neuroendocrine challenge studies pro- vide only an indirect way of ‘probing’ central 5-HT function.” In contrast, results from studies in animals provide strong evidence that thyroid status has a considerablee 151 uuoY Suysvojar-undonousy = ERY, ‘oUXoNPOAA = py, ‘osepXOVURUPONOM = OVI founTEYd An Kxoxp sys = Noowa[OPULAXOIPAY-S = VVIH-S ‘OUMMMEINYLOJ-P = NALI-P ‘pIny [eUIdsOIqoID = AS9 :suoNDIAaqGD paypUDIS-UON ‘furry imeayuBIs ou = — :oseaisop 1uRaYIUfs = f :osmoIU jUEDYrUS = | v0 amp LES ‘sxe pronyp- Are s10jdooas 2 LES Jo Ananysuos sonuos proxyne “ s oie, a. UIUOIOIIS Molecular Psychiatry‘Thyroid serotonin relationstip M Beret Impact in serotonergic neurotransmission in the adult brain. Exporimentally-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-HT,, 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 inhibi- tory autoreceptors on the serotonergic cell bodies and thus, reduce serotonin turnover in the cortical and sub- cortical projection areas of these serotonergic neurons. The value of direct measuroments 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-H. receptor density, an observation that reinforces the postulate that hypothy- roidism is associated with a reduced cortical sero- tonergic neurotransmission. ‘Thyroid hormone application may increase cortical Figure1 The thyroidbrain serotonin system interrelation- ship in adult animals. (a) Experimentally-induced hypothy- roidism. (b) Effects of thyroid hormone on the brain sero- tonin system, Molecular Psychiatry serotonergic neurotransmission via two independent mechanisms: (1) by reducing the sensitivity of 5-HT,. autoreceptors in the raphe area, thus disinhibiting cortical and hippocampal serotonin release; and (2) by increasing cortical 5-HT. receptor sensitivity, a poten- tially independent way of increasing 5-HT neuro- transmission (Figure 1). ‘These latter two potential mechanisms for thyroid hormone modulation of sero- tonin 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 immedi- ately.’?”? However, application of SSRIs also activates, presynaptic 5-HT,, autoreceptors located on sero- tonergic cell bodies in the raphe area and may thus inhibit serotonin release in the cortical projection areas.” Subsequently, an increase in frontal serotonin release is only found after prolonged SSRI appli: cation,” whon increased synaptic serotonin concen- trations in the brainstem induce a down-regulation of 5-HT,, autoreceptors, or after a drug-induced blockade of 5-HT,, receptors.”® This mechanism has been postu- lated to be responsible for the delayed antidepressive effects of SSRIs.** In accordance with this hypothesis, a blockade of 5-HT,, receptors would facilitate the antidepressive action of SSRIs in patients with major depression." A similar mechanism involving a desensitization of presynaptic 5-HT,, autoreceptors could be involved in the efficacy of thyroid hormones to accelerate and augment antidepressant agents. This could also explain why T, 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-HT,. receptor antagonist pindolol and of thy- roid hormones, and that both pindolol and T, are found to speed recovery from depression.”""" With respect to the potential second mechanism, it should be noted that reduced 5-HT; receptor sensitivity has been observed in most,’’-" although not all studies of patients with major depression."* Subsequently, treat- ment with clomipramine or SSRIs increased 5-H receptor sensitivity.***” Thus, thyroid hormone- induced increases in 5-HT receptor sensitivity might potentiate the effects of antidepressant drugs on the 5- HT, receptors, as has been demonstrated in studies with animals and humans,"**” However, a hypoth- esis of 5-HT, 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-chlorophenylpiperazino)."*** The observed effect might be mediated via various contributions of both 5- HTc and 5-HT,, receptor stimulation.""" Second, autoradiographic and brain imaging studies, measuring not the sensitivity but the density of 5-H, receptorsamong patients with major depression, observed sig- nificant decreases in frontocortical 5-HT; receptor availability after antidepressive drug treatment." 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.” Sandrini et aF* and Watanabe" that cortical 5-HT, receptor density ‘was reduced after thyroid hormone application, a pro- cedure which has been shown to increase the sensi- tivity of this receptor subtype.**"*"” 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 under- standing thyroid hormone effects on brain function, include post-receptor, transcriptional, and gene regu- latory 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 rogions.® Conversoly, in studies of euthyroid animals, treatment with T, decreased the abundance of the alpha-subunits of G, in synaptosomal membranes of the cerebral cortex." Impaired signal transduction via adenylate cyclase and inositol phos- phatase has also been demonstrated in the adult brain of hypothyroid rats. Hypothyroid rats also showed enhanced inhibition of adenylate cyclase in synaptoso- mal membranes by GTP." and decreased formation of inositol phosphate in response to the muscarinic chol- inergic agonist carbachol.” Thus, it appears that thy- roid 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 phospho- inositide-based signaling pathways involved in tran- scriptional activities in the adult CNS."°9"* ‘The molecular action of thyroid hormone is mediated through specific nuclear TH receptors (TRs) and 8 (B1, 62), functioning as ligand-dependont tran- scription factors that increase or decrease the expression of target genes.®* Although the two genes that encode the related TRe and TRB are differentially expressed, the two receptors usually coexist in the same cell type. The relative contribution of these two TTR genes encoding for TRe and TRB in mediating a particular T, 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 ‘Thyroid serotonin elatonship Ber a behavioral or neuroanatomical abnormalities com- pared with animals rendered hypothyroid by thyroid- ectomy"*" suggesting that other TR forms may com- pensate or substitute for lacking or defective receptors in these knock-out mouse models. In contrast, a 1 knock-in mouse model with a T, binding mutation in the TRB locus resulted in severe neuroanatomical and behavioral dysfunction (eg, abnormal hippocampal gone expression of brain-derived neurotrophic factor (BDNF), myelin basic protein (MBP), and tyrosine pro- toin kinase receptor B (T:KB), learning deficiency, and cerebellar dysfunction) indicating a specific and del- eterious action of unliganded ‘TR in the brain.” Recent studies have also indicated that the adult brain has various genetic loci that are responsive to thyroid hormones. Among the most extensively studied loci is RT3/neurogranin, a brain-specific gene encoding a protein kinase C substrate that binds calmo- dulin and is located in dendritic spines and forebrain neurons;"" in these studies, adult-onset hypothyroid- ism led to a decrease of RC3/neurogranin, an effect that ‘was reversible with T, treatment." Thyroid hormone also modulates glucose transport processes across the blood-brain barrier (BBB)"” and in astrocytes," and may alter the expression of glucose transporter one (GLUT-1) gene, the principal isoform responsible for glucose transport across the BBB.’ Furthermore, the effects of thyroid hormones on CNS gene expression have been demonstrated for various other neuroactive peptides, eg, TRH,’ corticotropin-releasing hormone (CRH),"®” brain-derived neurotrophic factor, nerve growth factor and neurotrophin 3," angiotensin- ‘ogen,'"® and several structural brain-specific gonos (og, myelin-associated glycoprotein, Pcp-2, microtubule- associated proteins)."** Of particular relevance is a recently reported interaction between thyroid and sero- tonin systems, indicating synergistic effects of T, and 5-HT,q tecoptors on hippocampal brain-derived neuro- trophic factor (BDNF) expression. T, administration prior to treatment with a 5-HT,, agonist caused a downregulation of hippocampal BDNF mRNA expression in adult rats." These molecular studies clearly indicate that thyroid hormones actively regu- late a broad spectrum of genes in the adult brain although the behavioral significance of such activity is unknown. Conclusions 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 pathogen- esis of depression we speculate that the serotonin sys- tem may be involved in the mood modulating effects of thyroid hormones among pationts with affective dis- orders. This hypothesis would explain why thyroid hormones are most effective in patients with affective disorders when administered as an adjunctive treat- 15315 ‘Thyroid serotonin rlaonship Baer ea ment 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.*° 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 neuro- transmitter systems thought to be involved in the regu- lation of mood including post-receptor and signal transducing processes, as well as gene regulatory mechanisms. Acknowledgments ‘We thank Georg Juckel, MD, and Faustino Lopez-Rodri- guez, PhD, MD, for comments on the manuscript. 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