Neuroendocrinology of stress and de pres sion

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1 Neuroendocrinology of stress and de pres sion W.-U.Weitbrecht Neurologic Clinic/KKH Gummersbach ac a demic teach ing hos pi tal of the Uni ver sity of Co logne Summary. The con cept and the re lated def i ni tions of stress were given by Wal ter Can non 1914 and Hans Selye Neuroendocrine an swer to stress nor mally is a mech a nism to adapt the or gan ism to dif fer ent in ter nal or ex ter nal con di tions. The main com po nents of the stress sys tem are the corticotropin-re leas ing hor mone (CRH) and lo cus coeruleusnorepinephrine/au to nomic sys tems and their effectors, the pi tu itary-ad re nal axis, and the limbs of the au to nomic sys tem. The ef fects of CRH are trans ferred by two spe cific re cep tors linked with pro tein G: CRH-R1 and CRH-R2. The main neg a tive feed back reg u la tion of hy - po tha lamic neuronal activity is performed by peripheral steroids. Different peptides as argenine- vasopressin ac ti vate the HPA sys tem. In hu man be ings atrial natriuretic pep tide (ANP) is the only neuromodulator with antianxiety ef fects that in hib its HPA ac tiv ity at mul - ti ple lev els. Ev i dence for in ter ac tions be tween the ner vous and im mune sys tems is dis cussed. Dis tur bances in the HPA-axis have an in flu ence of af fec tive state and cog ni tion. CRH ap - pears to play an im por tant role in reg u lat ing key neu ral sys tems in volved in con trol ling mood, anx i ety, feed ing be hav ior, and the in ter ac tions be tween stress and drug ad dic tion. The re cent de velopment of selective, small molecule CRH R1 receptor antagonists, which block the ef fects of CRH both in vi tro and in vivo, sug gest that these com pounds may be ef fec tive in the treat ment of affective and anxiety disorders. Keywords: stress, de pres sion, hy po tha lamic pi tu itary adrenocortical sys tem (HPA), corticotropin-re leas ing hor mone (CRH), atrial natriuretic pep tide (ANP) Neurologijos seminarai 2003; 2(18): IN TRO DUC TION The stress con cept is one of the most com monly ap plied con structs in men tal health. The con cept and the re lated def i ni tions of stress were given by Wal ter Can non 1914 and Hans Selye 1936 [7, 39, 43]. They dis cov ered that di - verse stim uli (stress ors) such as hun ger, thirst, cli ma tic changes, pain, and dif fer ent nox ious agents cause phys i o - log i cal changes in the an i mal such as re lease of ad re nal hor mones. The term stress to day is used in much broader sense [3, 47]. It im pli cates phys i cal and psy chic stress ors. Neuroendocrine an swer to stress nor mally is a mech a nism to adapt the or gan ism to dif fer ent in ter nal or ex ter nal con - di tions. Emo tional or phys i cal stress in duces a cas cade of changes which leads to a fine tuned an swer of the or gan - ism. Ac ti va tion of sympathicus re sults in higher at ten tion fo cussed to the trig ger and less re pro duc tive ac tiv ity. Whether the stress ing con di tion is harm less or harm ful de - pends on the way an or gan ism is cop ing with the threat en - ing sit u a tion and whether it re gains to ho meo sta sis. A very im por tant part of cop ing strat egy is to fin ish the an swer of the or gan ism when the stressor has passed. If the or gan ism Au thor s ad dress: Assoc.Prof.Dr.W.-U.Weitbrecht Neurologische Klinik/KKH Wil helm-breckow-allee 20 D Gummersbach Germany weitbrecht@kkh-gummersbach.de is not able to finish stress-reaction, pathological alterations may re sult. This con di tion may be caused by chronic stress ex po si tion. With this im pli ca tions stress may be mea sured by mon i tor ing terms of be hav ioural and phys i o log i cal al - ter ations that might be in dic a tive for the in di vid ual s state of well-being. THE STRESS-SYS TEM The stress system (figure 1) coordinates the generalized stress re sponse, which takes place when a stressor of any kind ex ceeds an in di vid ual thresh old. The main com po - nents of the stress sys tem are the corticotropin-re leas ing hor mone and lo cus coeruleus-norepinephrine/au to nomic sys tems and their effectors, the pi tu itary-ad re nal axis, and the limbs of the au to nomic sys tem. The stress sys tem is sum ma rized by most of the au thors as the hy po tha lamic pi - tu itary adrenocortical (HPA) stress sys tem. Ac ti va tion of the stress sys tem nor mally leads to be hav ioural and pe riph - eral changes that im prove the abil ity of the or gan ism to ad - just ho meo sta sis and in crease its chances for sur vival [8, 44]. Corticotropin-re leas ing hor mone (CRH) is the brain neuropeptide which co or di nates the en do crine, au to nomic and be hav ioural re sponses to stress. CRH pro duc ing neu - rons are lo cal ized mainly in the paraventricular nu cleus of the hy po thal a mus. Se ro to nin (5-hydroxytryptamine, 5-HT)-con tain ing neu rons in the midbrain di rectly 22

2 gluconeogenesis + lipolysis + proteolysis + insulin-resistence + Fig ure 1. The stress-sys tem ACTH corticoid hormones CRH innervate corticotropin-re leas ing hor mone (CRH)-con - tain ing cells lo cated in paraventricular nu cleus of the hy - po thal a mus. Serotonergic in puts into the paraventricular nu cleus me di ate the re lease of CRH, lead ing to the re lease of adrenocorticotropin, which trig gers glucocorticoid se - cre tion from the ad re nal cor tex [22]. En do crine ac tive CRH is co lo cal ized with arginine-vasopressin. Ovine CRH is a pep tide that con sists of 41 amino ac ids [50]. CRH is re leased by axon ter mi nals that pro ject to the me dian em - i nence and is trans ported by the hypophyseal por tal sys tem to the an te rior pi tu itary, where it in duces the syn the sis of adreno-corticotrope-hor mone (ACTH), ß-endorphine, ß-lipo tropin, and al pha-melanocyte-stim u lat ing-hor mone/ alpha-melanotropin [2]. ACTH activates adrenal cortex re - sult ing in an in crease of glucocorticoids. CRH not only ac - tivates the hypothalamic-pituitary-adrenocortical stressre sponse sys tem, it also has a neu ro trans mit ter func tion in the brain. Pro jec tions to brainstem and spi nal cord ac ti vate autonome ner vous sys tem [47]. Ex per i men tal data showed ev i dence for the par tic i pa tion of CRH-syn the siz ing neu - rons in hy po thal a mus and medullary catecholamin ergic neu rons in the cen tral or ga ni za tion of re sponses to audiogenic stress stim uli [23] and intraventricular ad min - istered CRH elevates plasma catecholamine concentration and in creases ar te rial pres sure and heart rate [19]. CRH re - cep tors have been iden ti fied also in brain ar eas in volved in cog ni tive func tion as well as in limbic ar eas [13]. Fur ther more CRH neu rons in the paraventricular nu cleus and ventromedial hy po tha lamic nu cleus are an im por tant me - di a tor for leptin that con trib ute to reg u la tion of feed ing, ad - i pos ity, and ex pres sion of un cou pling pro tein [33]. Re sults of an i mal mod els sug gest that growth hor mone se cre tion in duced by opioid pep tides via GABAergic mech a nisms is me di ated, at least in part, by hy po tha lamic GRH [34]. The ef fects of CRH are trans ferred by two spe cific re - cep tors linked with pro tein G: CRH-R1 and CRH-R2. blood pressure + pulse + glucose + gastrointestinal activity immunologic system +/- libido - sleep - appetite - fear + psychomotoric +/- Neuroendocrinology of stress and de pres sion CHR-R1 re cep tors are nearly solely ex pressed in the fron tal cor tex, the cholinerg basal forebrain, the cholinerg nu clei or brain stem, colliculus su pe - rior, basal lat eral nu cleus amygdala, cerebellum, nu - cleus trigemini, and an te - rior pi tu itary lobe. CRH-R2 re cep tor pre dom i nates in paraven tricular neu rons, lateral septum, central and me dial parts of nu cleus amygdalae, and serotonin - erg nu cleus raphe. Mixed ex pres sion of re cep tors is found in the bulbus olfactorius, hip po cam pus, stria terminalis, and the periaquaeductal grey [6]. Extracerebral CRH re cep - tors were de tected in pla centa, myometrium, decidua, and fe tal mem branes. The pres ence of CRH re cep tors was also dem on strated on res i dent macrophages and on en do the lial cells. CRH re cep tor 1 mrna was de tected in all tis sues in - ves ti gated by RT-PCR, whereas CRH re cep tor 2 mrna was re stricted to myometrium and de cid uas [55]. The CRH 1 re cep tor plays the most crit i cal role in me di at ing the ACTH re sponse to shocks, al co hol and lipopoly sacchari - de, whereas the in flu ence of CRF(2) re mains sub tle [40]. CRH re lease of the HPA axis is reg u lated by dif fer ent pathways. Corticosterone appears capable of interacting with at least two dif fer ent neuronal mech a nisms to reg u late CRH mrna lev els: one is clearly seen in paraventricular neurosecretory neu rons, where in creas ing plasma corticosteroid re duces CRH mrna lev els; the other, seen in neu rons in the cen tral nu cleus of the amygdala, acts to in crease them. Al though feed back reg u la tion of hy po tha - lamic neuronal ac tiv ity by pe riph eral ste roids is a well-es - tab lished tenet of en do cri nol ogy, data show mod u la tion of the intrahypothalamic ac tions of CRH by ad re nal and sex ste roids. Cir ca dian in flu ences play also an im por tant role in or ga niz ing homeostatic pro cesses, and they have an in - flu ence on CRH gene ex pres sion too [1, 30, 42, 52]. Different peptides as argenine-vasopressin activate the HPA sys tem. In hu man be ings atrial natriuretic pep tide (ANP) is the only neuromodulator with antianxiety ef fects that in hib its HPA ac tiv ity at mul ti ple lev els. The myocytes of the atrium pro duce ANP. But it is also found in dif fer ent brain re gions. Pro-ANP plasma lev els are in de pend ently and in versely re lated to anx i ety. Even in se vere cor o nary hat fail ure with se verely com pro mised qual ity of life, anx i - ety tends to de crease with high pro-anp lev els. This might be part of a neg a tive feed back loop lim it ing psy cho log i cal dis tress [24]. ANP causes a dose-de pend ent in hi bi tion of CRH-41 re lease from the rat hy po thal a mus in vi tro [28] and may per haps be func tion ally sig nif i cant cortico - 23

3 W.-U.Weitbrecht trophin-re lease in hib it ing fac tor [18]. CRH-stim u lated ACTH and cortisol se cre tion is sig nif i cantly re duced by the ad min is tra tion of ANP in com par i son to sa line. Tis sup ports the view that ANP may also be in volved in the fre - quently ob served nonsuppression af ter dexa meth a sone dur ing de pres sion [48]. So phys i o log i cal stim uli pres ent to be a com plex mix ture of humoral and neu ral sig nals to the CNS, in te gra tion of these sig nal types is the most crit i cal as pect of pep tide me tab o lism [11, 31, 49]. Over a lon ger time ad min is tered CRH and vasopressin in an i mal mod els reg u late mineralocorticoid and glucocorticoid re cep tors in hip po cam pus and an te rior pi tu itary. This re veals an other im por tant func tion of CRH and vasopressin, which could be rel e vant to un der stand stress ad ap ta tion [27]. Two ste roid re cep tors trans fer corticoid level into cell/me tab o lism ac tiv ity: the glucocorticoid und the mineralocorticoid re cep tor. The mineralocorticoid re cep - tor has a 10 fold higher ac tiv ity than the glucocorticoid re - cep tor and is re spon si ble for the tonic and basal ac tiv ity. The glucocorticoid re cep tor is ac ti vated cir ca dian and is re spon si ble for the stress re sponse [12]. The main neg a tive feed back reg u la tion of hy po tha lamic neuronal ac tiv ity and ACTH re lease is per formed by pe riph eral ste roids. The ste - roid hor mone ef fect may be clas si fied into two dif fer ent ac tions: ef fects on the ge nome and ef fects on mem brane re cep tors [47]. STRESS AND IM MU NO LOGIC SYS TEM Ev i dence for in ter ac tions be tween the ner vous and im - mune sys tems arises from a num ber of ex per i men tal ob ser - va tions: the be hav ioral con di tion ing of im mune re sponses, the ef fects of stim u la tion or le sion of brain sites on im mune sys tem func tion, the ef fects of stress ors on im mune re - sponses and tu mor growth, and phys i o log i cal and neurochemical changes in the brain dur ing im mune re - sponses. The links be tween the ner vous and im mune sys - tems in clude glucocorticoids se creted from the ad re nal gland, cate chol amines and neuropeptides se creted by sym - pathetic terminals and the adrenal medulla, certain pitu - itary and go nadal hor mones, and polypeptides pro duced by cells of the im mune sys tem. The ef fect of gluco - corticoids is not ex clu sively immunosuppressive, nor is it ad e quate to ex plain all the ef fects of stress. Hu man macrophages are stim u lated in vi tro to phagocytosis by adren a line/noradrenaline (al pha-re cep tor) but not by gluco corticoids at phys i o log i cal lev els. High lev els of gluco corticoids in hibit phagocytosis [53, 54]. The ef fects of opi ates on im mune func tion are com - plex; in vi tro, en dog e nous opi ates most of ten fa cil i tate im - mune ac tiv ity, but in vivo, opi ates ap pear to in hibit im - mune re sponses and im pair tu mor re jec tion. The in vi tro ef fects are rarely pre vented by naloxone pre treat ment and ap pear to re quire the in teg rity of the C- rather than the N-ter mi nal of beta-en dor phin, sug gest ing a nonopiate char ac ter. In fec tions or the ad min is tra tion of an ti gens in - crease cir cu lat ing con cen tra tions of glucocorticoids and ac ti vate ce re bral catecholaminergic me tab o lism, es pe - cially in the hy po thal a mus. These re sponses sug gest that chal lenges to the im mune sys tem are phys i o logic stress ors. Interleukin-1 (IL-1) pro duced by im mune cells may be the me di a tor of these ef fects, thus act ing as an immunoneu - rotransmitter. The ce re bral re sponses sug gest that the brain can mon i tor the prog ress of im mune re sponses. IL-1 and the glucocorticoids to gether may form a reg u la tory feed back mech a nism for im mune re sponses [16]. Acute stress also leads to mast cell-de pend ent se rum IL-6 in - crease that may help ex plain stress-re lated cor o nary in - flam ma tion [26]. CRH has also been found in di verse in flam ma tory sites, the myometrium, the endometrium, and the pla centa. Tra di tion ally, hy po tha lamic CRH has been con sid ered to act in di rectly in an anti-in flam ma tory fash ion, since the end prod uct of the hy po tha lamic-pi tu itary-ad re nal axis is cortisol, a well-known anti-in flam ma tory com pound. How ever, CRH pro duced at pe riph eral in flam ma tory sites may par tic i pate in an auto-/paracrine stim u la tion of in - flam ma tion. CRH in in flam ma tory sites seems to be in - volved in the ac ti va tion of the Fas/Fas ligand sys tem. Fur - ther more, lo cally pro duced em bry onic and endometrial CRH plays a role in both the asep tic in flam ma tory pro cess of im plan ta tion and the anti-re jec tion pro cess that pro tects the fe tus from the ma ter nal im mune sys tem. There are two types of G pro tein-cou pled CRH re cep tors, type 1 and 2. Pyrro lopyrimidine com pounds, such as antalarmin, have been de vel oped as CRH re cep tor an tag o nists. The sys - temic administration of antalarmin blocks pituitary CRH re cep tors and the CRH-in duced se cre tion of adreno - cortico tropin [29]. Un der con di tions of fre quent ex po sure to acute stress and/or chronic, long-term ex po sure to stress, the LHPA axis be comes dys func tional and in the pro cess fre quently over pro duces both CRH and glucocorticoids, which re - sults in many mild to se verely toxic side ef fects. Bidirec - tional com mu ni ca tion be tween the LHPA axis and im - mune/inflammatory systems can dramatically potentiate these side ef fects and cre ate en vi ron ments in the CNS and pe riph ery ripe for the trig ger ing and/or pro mo tion of tis sue de gen er a tion and dis ease [32]. STRESS AND DE PRES SION Mood and anx i ety dis or ders are highly prev a lent psy chi at - ric dis or ders, es pe cially in women, and they are as so ci ated with sig nif i cant mor bid ity and mor tal ity. A con sid er able literature indicates that vulnerability to depression and anx i ety dis or ders is mark edly in creased by child hood abuse, e.g., phys i cal, sex ual, and psy cho log i cal abuse, as well as adult hood stress ors, e.g., death of a spouse. Re cent re search on the ef fects of ad verse early life ex pe ri ences on cen tral ner vous sys tem (CNS) stress sys tems has pro vided a greater un der stand ing of the link be tween child hood 24

4 Neuroendocrinology of stress and de pres sion abuse and sus cep ti bil ity to mood and anx i ety dis or ders. Specifically, early life traumatic events, occurring during a pe riod of neuronal plas tic ity, ap pear to per ma nently ren der neuroendocrine stress re sponse sys tems supersensitive. These phys i o log i cal maladaptations likely rep re sent long- term risk fac tors for the de vel op ment of psychopa - thology af ter ex po sure to ad di tional stress [37]. The car di - nal clinical manifestations of major depression with mel - an cholic fea tures in clude sus tained anx i ety and dread for the fu ture as well as ev i dence of phys i o log i cal hyper - arousal (e.g., sus tained hy per ac tiv ity of the two prin ci pal effectors of the stress re sponse, the corticotropin-re leas - ing- hor mone, or CRH, sys tem, and the lo cus ceruleusnore pinephrine sys tem (LC-NE)). Sus tained stress sys tem ac ti va tion in mel an cholic de pres sion is thought to con fer both be hav ioral arousal as well as the hypercortisolism, sym pa thetic ner vous sys tem ac ti va tion, and in hi bi tion of pro grams for growth and re pro duc tion that con sis tently oc cur in this dis or der. Data also sug gest that ac ti va tion of the CRH and LC sys tems in mel an cho lia are in volved in the long-term med i cal con se quences of de pres sion such as pre ma ture cor o nary ar tery dis ease and os teo po ro sis, the two- three-fold pre pon der ance of fe males in the in ci dence of ma jor de pres sion, and the mech a nism of ac tion of an ti - de pres sant drugs. In ad di tion, re cent data re veal im por tant bidirectional in ter ac tions be tween stress-sys tem hor monal fac tors in de pres sion and neu ral sub strates im pli cated in many dis crete be hav ioral al ter ations in de pres sion (e.g., the me dial prefrontal cor tex, im por tant in shift ing af fect based on in ter nal and ex ter nal cues, the mesolimbic dopamin ergic re ward sys tem, and the amygdala fear sys - tem). Many data in di cate that the hypersomnia, hyper - phagia, leth argy, fa tigue, and rel a tive ap a thy of the syn - drome of atyp i cal de pres sion are as so ci ated with con com i - tant hypofunctioning of the CRH and LC-NE systems. Dis tur bances in the HPA-axis have an in flu ence of af - fec tive state and cog ni tion. Fig ure 2 shows a model of in - ter re la tion be tween HPA-axis and be hav ioural sta tus. In af fec tive dis or ders a num ber of neuropeptides seem to be caus ally in volved in de vel op ment and course of ill ness, es - pe cially corticotropin re leas ing hor mone (CRH), vaso - pressin and sub stance P, whose re cep tors are now tar geted with small mol e cules de signed to re duce de pres sive and anx i ety symp toms. CRH ap pears to play an im por tant role in reg u lat ing key neu ral sys tems in volved in con trol ling mood, anx i ety, feed ing be hav ior, and the in ter ac tions be - tween stress and drug ad dic tion. CRH-ex press ing cells and their tar get neu rons pos sess ing CRH re cep tors (CRH R1 and CRH R2) are dis trib uted through out the limbic sys tem. results of several investigations indicate that CRH R1 regu la tion in volves both oc cu pancy of this re cep tor by its ligand, as well as down stream cel lu lar ac ti va tion and sug gest that stress-in duced per tur ba tion of CRH-CRH R1 sig nal ing may con trib ute to ab nor mal neuronal com mu ni - ca tion af ter some stress ful sit u a tions [4, 20, 38]. Al though not ex actly neuropeptides, also neurotrophins, may have a dis tinct role in an ti de pres sant ac tion and pos si bly also in cau sa tion of de pres sion. Schizo phre nia-like symp toms are Threat of control Flight and fightamygdala activation of the sympathicoadreno-medullary system behavioral activity Stimulus (stressor) Coping pattern (genetic disposition, early experience) caused by neurotensin (NT), sup port ing the no tion that drugs in ter fer ing with NT sys tem are po ten tial antipsy - chotics [9, 15, 25]. CRH has an anxiogen ef fect in an i mal mod els [17]. CRH ra tio also re sults in changes of sleep-en do crine ac tiv ity. It is thought that the change of this ra tio in fa vour of CRH con trib utes to ab er ra tions of sleep dur ing age ing and de pres sion (shal low sleep, blunted GH and el e vated cortisol). There are hints that CRH pro motes rapid eye move ment sleep (REMS) [45] % of the pa tients with ma jor de pres sion showed only low changes of basal, non stim u lated lev els of ACTH and cortisol. Anal y sis of cir ca dian peeks re sulted in more peeks and higher lev els than in healthy peo ple [14]. In creased ad re nals as an in di - ca tion to chronic hy per ac tiv ity were found in pa tients with ma jor de pres sion [41]. This data sug gest that CRH over - drive and cortisol over pro duc tion may play a patho genic role in the oc cur rence of cer tain types of de pres sion, di - rectly and/or in di rectly, i.e. by in duc tion or ex ac er ba tion of dis tur bances in monoaminergic trans mis sion [51]. THERAPEUTIC PERSPECTIVE Loss of control depressionhippocampus- Septumactivation of the pituitary-adrenocortical systembehavioral inactivity Figure 2. Cop ing and pre dict abil ity con cept for stress con trol and depression (mod i fied: Borell 2001) These data in di cate the pos si bil ity for an en tirely dif fer ent ther a peu tic strat egy than that used in mel an cho lia for the treat ment of atyp i cal de pres sion, and they sug gest that this sub type of ma jor de pres sion will be as so ci ated with its own unique rep er toire of long-term med i cal con se quences. Some an ti de pres sant drugs can di rectly in flu ence cortico - tropin-re leas ing hor mone (CRH) gene ex pres sion. Imi pra - mine and fluoxetine, but not tianeptine, in hibit the hu man CRH gene pro moter ac tiv ity [5]. CRH-R1-de fi ciency re - sults in re duced hy po tha lamic-pi tu itary-adrenocortical axis ac tiv ity, in en hanced syn the sis of se ro to nin dur ing basal con di tions, and in an aug mented re sponse in extra - cellular lev els of se ro to nin to stress. These data pro vide further evidence for the intricate relationship between cortico tropin-re leas ing hor mone and se ro to nin and the im - por tant role of the CRH-R1 herein [36]. The re cent de vel - op ment of se lec tive, small mol e cule CRH R1 re cep tor an - tag o nists, which block the ef fects of CRH both in vi tro and 25

5 W.-U.Weitbrecht in vivo, sug gest that these com pounds may be ef fec tive in the treat ment of af fec tive and anx i ety dis or ders. Early ev i - dence in di cates that these agents pos sess anxio lyt ic and an - ti de pres sant ac tiv ity in an i mal be hav ioral mod els [10, 21, 35, 46]. An other ther a peu tic pos si bil ity are drug which re - duce cortisol se cre tion [47]. Gauta Priimta spaudai Lit er a ture 1. Almeida OF, Hassan AH, Holsboer F. Intrahypothalamic neuroendocrine ac tions of corticotropin-re leas ing fac tor. Ciba Found Symp 1993; 172: Axelrod J, Reisine TD. Stress hor mones: their in ter ac tion and reg u la tion. Sci ence 1984; 224: Borell EH. The bi ol ogy of stress and its ap pli ca tion to live - stock hous ing an trans por ta tion as sess ment. J Anim Sci; 79(E. Suppl.): E Brunson KL, Grigoriadis DE, Lorang MT, Baram TZ. 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Normalus neu ro en - do kri ni nis atsakas á stresà tai organizmo adaptacijos me cha niz - mas ávairiems vidiniams bei iðorinës aplinkos veiksniams. Svar - biau si stresinës sistemos komponentai kortikotropinà at pa lai - duojantis hormonas ir melsvojo branduolio-noradrenalino-auto - nominë sistema bei jø efektoriai, pagumburio-hipofizës-antinks - èiø sistema, autonominës nervø sistemos limbinë dalis. Kor ti ko - tro pi nà atpalaiduojantis hormonas veikia dviejø tipø specifinius re cep to rius, susijusius su proteinu G: tai CRH-R1 ir CRH-R2. Pa - grin di næ slopinamàjà pagumburio neuronø reguliacijà gráþ ta mo - jo ryðio principu atlieka periferiniai steroidiniai hormonai. Pa - gum bu rio- hipofizës-antinksèiø sistemà aktyvuoja ávairûs pep ti - dai, pvz., argininas-vazopresinas. Þmoniø organizme vienintelis neuromoduliatorius, pasiþymintis anksiolitiniu poveikiu ir slopi - nan tis pagumburio-hipofizës-antinksèiø sistemos aktyvumà ávai riuo se lygiuose, tai prieðirdþiø natriuretinis peptidas. Straips ny je aptariami nervø sistemos ir imuniteto sàveikos as - pek tai. Pagumburio-hipofizës-antinksèiø sistemos pusiausvyros su tri ki mas turi átakos afektinei bûklei ir kognityvinëms funk ci - joms. Kortikotropinà atpalaiduojantis hormonas atlieka svarbø vaid me ná, reguliuodamas NS sritis, kurios dalyvauja nuotaikos, ne ri mo, maitinimosi, elgesio kontrolëje, daro átakà pa to ge ne zi - niam ryðiui tarp streso ir piktnaudþiavimo medikamentais. Pa sta - ruo ju metu atrastos selektyvios maþos masës molekulës CRH-R1 receptoriø antagonistai, blokuojantys ðiuos receptorius in vivo ir in vi tro. Ðios medþiagos gali tapti efektyviais vaistais afektiniams bei nerimo sutrikimams gydyti. Raktaþodþiai: stresas, depresija, pagumburio-hipofizës-an - tinks èiø sistema, kortikotropinà atpalaiduojantis hormonas, prie - ðir dþiø natriuretinis peptidas 27