Histamine and prostaglandin interaction in regulation of oxytocin and vasopressin secretion.

Prostaglandins and histamine in the hypothalamus are involved in the regulation of oxytocin and vasopressin secretion, and appear to be involved in the mediation of pituitary hormone responses to immunochallenges. Therefore, we investigated in conscious male rats: (i) whether blockade of H1 or H2 receptors affected the oxytocin and vasopressin responses to prostaglandins and (ii) whether blockade of prostaglandin synthesis affected the oxytocin and vasopressin responses to histamine or to Escherichia coli lipopolysaccharide (LPS), in order to determine any interaction between prostaglandins and histamine in the hypothalamus. Oxytocin secretion was dose-dependently stimulated by intracerebroventricular infusion of 1 or 5 microg of PGE1, PGE2 or PGF2alpha, with PGE2 being the most potent of the compounds used. Prior central infusion of the H1 receptor antagonist mepyramine or the H2 receptor antagonist cimetidine significantly inhibited the oxytocin response to all three prostaglandins by approximately 50%. Vasopressin secretion was increased by PGE1 but not by PGE2 or PGF2alpha. The stimulatory effect of PGE1 was almost annihilated by prior administration of mepyramine or cimetidine. Central infusion of histamine or immunochallenge with LPS administered intraperitoneally increased oxytocin and vasopressin secretion four- and two-fold, respectively. Pretreatment with systemic injection of the prostaglandin synthesis inhibitor indomethacin dose-dependently reduced the oxytocin response and prevented the vasopressin response to histamine or LPS. We conclude that histamine and PGE1, PGE2 or PGF2alpha interact in the regulation of oxytocin secretion, whereas histamine and only PGE1 interact in the regulation of vasopressin secretion. Furthermore, histamine as well as LPS may affect oxytocin and vasopressin neurones via activation of prostaglandins, probably in the hypothalamic supraoptic nucleus.

The role of hypothalamic histamine in leptin-induced suppression of short-term food intake in fasted rats.

OBJECTIVE: Leptin suppresses food intake; however, the precise mechanism is not fully understood. Histamine (HA), which acts as a neurotransmitter in the central nervous system, has also been shown to be involved in feeding and exerts an inhibitory effect through activation of H(1) receptors. Therefore, we studied the possible role of HA in short-term leptin-induced suppression of food intake. METHODS: We studied the 6-h feeding response of overnight-fasted adult (200 g) male Wistar rats to leptin and the HA synthesis inhibitor alpha-fluoromethylhistidine (alpha-FMH). Levels of transcription for neuropeptide Y (NPY) and corticotropin-releasing hormone (CRH), as well as hypothalamic content of HA and the HA metabolite telemethyl-HA were investigated. RESULTS: Central administration of leptin (3, 5 and 10 microg at 09:00 h) in fasted rats caused a decrease in food intake. In contrast, central administration of alpha-FMH (11, 22 and 112 microg at 09:00 h) increased food intake. Prior administration of alpha-FMH prevented the leptin-induced decrease in food intake. Leptin decreased hypothalamic histamine content, while increasing the ratio between telemethyl-HA and HA, indicating that leptin reduces HA metabolism. Finally, alpha-FMH suppressed basal and leptin-induced CRH expression while stimulating NPY expression in fasted rats. CONCLUSION: Histamine is involved in leptin-induced inhibition of food intake. The role of histamine may be mediating, i.e. leptin may directly activate and/or change the metabolism of the histaminergic system. Alternatively, the histaminergic system may be involved in a permissive manner.

Effect of interleukin 1beta on the HPA axis in H1-receptor knockout mice.

OBJECTIVES AND METHODS: Circulating cytokines such as interleukin-1 (IL-1), and tumor necrosis factor-alpha as well as lipopolysaccharide (LPS) are potent ACTH secretagogues, acting via stimulation of corticotropin-releasing hormone (CRH) and vasopressinergic neurons in the paraventricular nucleus of the hypothalamus (PVN). Histamine (HA) has been shown to stimulate ACTH secretion in rats, an effect in part mediated by CRH and arginine vasopressin (AVP). We have previously shown that inhibition of neuronal HA synthesis or central blockade of H(1) receptors (H(1)R) decreased the ACTH response to LPS in male rats. To further elucidate the role of neuronal HA in cytokine-induced activation of the HPA axis, we compared the effect of H(1)R knockout on IL-1beta-induced ACTH secretion in adult male mice. RESULTS: In H(1)R knockout mice, ACTH secretion increased from basal levels of 261 to 492 pmol/l in response to IL-1beta whereas the cytokine-induced ACTH secretion increased from 140 to 406 pmol/l in wild-type mice. Plasma corticosterone (CORT) rose from basal levels of 99 to 831 nmol/l in knockout mice upon IL-1beta stimulation, whereas in wild-type mice CORT levels rose from 112 to 841 nmol/l. There was no significant difference in IL-1beta-stimulated plasma ACTH or CORT levels between wild-type and knockout mice. Furthermore, there was no significant difference in basal or IL-1beta-stimulated hypothalamic levels of histamine and tele-methyl-histamine between wild-type and knockout mice. HDC gene expression was significantly lower in knockout mice than in wild-type mice both under basal and IL-1beta-stimulated conditions, while there were no significant differences in CRH gene expression in the PVN in knockout mice under basal and IL-1beta-stimulated conditions. Increased basal expression of AVP in the PVN of knockout mice was observed in this study compared to wild-type mice. CONCLUSION: We conclude that the lack of the gene for histamine H(1)R does not seem to be crucial for the ACTH and CORT response to IL-1beta, either due to possible functional compensation in the H(1)R knockout mouse or due to activation of pathways other than the neuronal histaminergic system.

Histaminergic and catecholaminergic interactions in the central regulation of vasopressin and oxytocin secretion.

Activation of histaminergic and noradrenergic/adrenergic neurons in the brain stimulates the release of the neurohypophysial hormones arginine vasopressin (AVP) and oxytocin (OT) and are involved the mediation of the hormone responses to physiological stimuli such as dehydration and suckling. We therefore investigated whether the two neuronal systems interact in their regulation of AVP and OT secretion in conscious male rats. When administered intracerebroventricularly (i.c.v.), histamine (HA) as well as the H1 receptor agonist 2-thiazolylethylamine or the H2 receptor agonist 4-methylHA stimulated AVP and OT secretion. Prior i.c.v. infusion of antagonists specific to alpha or beta adrenergic receptors or their subtypes did not significantly affect the hormone response to HA or the histaminergic agonists. Infused i.c.v. norepinephrine (NE) or epinephrine (E) increased AVP and OT secretion. Prior i.c.v. infusion of the H1 receptor antagonist mepyramine or the H2 receptor antagonist cimetidine significantly inhibited the AVP and OT responses to NE and the AVP response to E, whereas only cimetidine inhibited the OT response to E significantly. Systemic pretreatment with imetit, which by activation of presynaptic H3 receptors inhibits neuronal synthesis and release of HA, decreased the AVP and OT responses to NE and E significantly. In the doses used, HA and E had no significant effect on mean arterial blood pressure. NE increased mean arterial blood pressure 10% at 1 and 2.5 min, whereafter the blood pressure returned to basal level within 10 min. The results indicate that noradrenergic and adrenergic neurons stimulate AVP and OT secretion via an involvement of histaminergic neurons, which may occur at magnocellular neurons in the supraoptic and paraventricular nuclei of the hypothalamus. The stimulatory effect of the amines on neurohypophysial hormone secretion seems to be independent of a central action on blood pressure. In contrast, a functionally intact noradrenergic and adrenergic neuronal system seems not to be a prerequisite for a HA-induced release of AVP and OT. The present findings further substantiate the role of histaminergic neurons in the central regulation of neurohypophysial hormone secretion.

Effect of selective blockade of catecholaminergic alpha and beta receptors on histamine-induced release of corticotropin and prolactin.

We investigated the role of adrenergic receptors in histamine (HA)-induced release of corticotropin (ACTH) and prolactin (PRL) in conscious male rats. Specific alpha- or beta-receptor antagonists were administered intracerebroventricularly in doses of 1 mmol at time -20 min, and HA (270 nmol), the H1 receptor agonist 2-thiazolylethylamine (2-TEA; 2,180 nmol) or the H2 receptor agonist 4-methylHA (4-MeHA; 790 nmol) were administered intracerebroventricularly at -15 min. The animals were decapitated at 0 min, and plasma was analyzed for ACTH and PRL. Administration of HA and the histaminergic agonists stimulated ACTH secretion equally, while only HA and the H2 receptor agonist stimulated PRL secretion. Pretreatment with the adrenergic receptor antagonists had no effect on the ACTH response to the histaminergic compounds. In contrast, the PRL response to HA or 4-MeHA was inhibited or prevented by the alpha-receptor antagonists phenoxybenzamine and phentolamine, the alpha1-receptor antagonist prazocin, the beta-receptor antagonist propranolol and the beta1-receptor antagonist atenolol, whereas the alpha2-receptor antagonist yohimbine or the beta2-receptor antagonist ICI-118-551 had no effect. The study indicates that histaminergic neurons interact with the catecholaminergic neuronal system in regulation of PRL secretion, and that this interaction is dependent upon activation of alpha1- and beta1-receptors. In contrast, histaminergic neurons stimulate ACTH secretion independently of adrenergic receptor activation.

Serotonergic involvement in stress-induced ACTH release.

We investigated the involvement of serotonin (5-HT) and 5-HT receptors in mediation of stress-induced ACTH secretion in adult male rats, which were pretreated by 5-HT antagonists before restraint-, ether-, cold swim-stress or endotoxin. All stressors potently increased plasma ACTH. Lesion of 5-HT neurons with 5, 7-dihydroxytryptamine injected intracerebroventricularly, into the paraventricular nucleus or into the raphe nuclei, inhibited the restraint stress-induced ACTH response by 50%. Restraint increased the content of 5-HT and its metabolite 5-hydroxyindole acetic acid, in the raphe nuclei, whereas the other stressors had no such effect. Pretreatment with the 5-HT1A receptor antagonist WAY 100635 inhibited the restraint stress- and endotoxin-induced ACTH secretion by 50%. The 5-HT1+2 antagonist methysergide or the 5-HT2 antagonist ketanserin inhibited the restraint- or ether stress-induced ACTH response, and eliminated the endotoxin-induced ACTH response. The 5-HT2 receptor antagonist LY 53857 blocked only the endotoxin-induced ACTH response. Pretreatment with the 5-HT3 receptor antagonist ondansetrone had no effect on stress-stimulated ACTH secretion. The 5-HT3+4 receptor antagonist tropisetrone inhibited the restraint- and ether stress-induced response. The ACTH response to swim stress was not affected by any of the antagonists used. It is concluded that the 5-HT1A, the 5-HT2A and the 5-HT2C receptor, but not the 5-HT3 receptor are involved in the stress-induced ACTH secretion. An involvement of the 5-HT4 receptor is possible. Furthermore, that serotonergic neurons in the raphe nuclei are activated during restraint stress, and that these neurons and neurons in PVN of the hypothalamus, are important for the mediation of the restraint stress-induced ACTH response.

Neuronal histamine and expression of corticotropin-releasing hormone, vasopressin and oxytocin in the hypothalamus: relative importance of H1 and H2 receptors.

Centrally administered histamine (HA) stimulates the secretion of the pro-opiomelanocortin-derived peptides ACTH and beta-endorphin as well as prolactin. The effect of HA on secretion of these adenohypophysial hormones is indirect and may involve activation of hypothalamic neurons containing corticotropin-releasing hormone (CRH), arginine-vasopressin (AVP) or oxytocin (OT). We studied the effect of activating central HA receptors by central infusion of HA, HA agonists or antagonists on expression of CRH, AVP and OT mRNA in the hypothalamic paraventricular (PVN) and supraoptic (SON) nuclei. Intracerebroventricular infusion of HA (270 nmol), the H1-receptor agonist 2-thiazolylethylamine or the H2-receptor agonist 4-methylhistamine increased the level of CRH mRNA in the PVN, and OT mRNA in the SON. In contrast, none of these compounds had any effect on expression of AVP mRNA in the PVN or SON. Administration of the H1-receptor antagonist mepyramine or the H2-receptor antagonist cimetidine had no effect on basal expression of CRH, AVP or OT mRNA in the PVN and/or SON except for a slight inhibitory effect of cimetidine on CRH mRNA expression in the PVN. Pretreatment with mepyramine or cimetidine before HA administration inhibited the HA-induced increase in OT mRNA levels but had no effect on the HA-induced increase in CRH mRNA levels in the PVN. We conclude that HA stimulates hypothalamic CRH and OT neurons by increasing mRNA levels, and this effect seems to be mediated via activation of both HA H1 and H2 receptors.

Dehydration-induced renin secretion: involvement of histaminergic neurons.

Renin secretion is controlled locally in the kidneys as well as via central neuronal mechanisms. The neuronal mechanisms are not fully understood but may involve the neurotransmitter histamine (HA) since centrally infused HA stimulates renin secretion. This, however, does not prove that HA is of any physiological importance for the regulation of renin secretion. Dehydration is a physiological stimulus of renin secretion and, therefore, we studied the possible role of hypothalamic histaminergic neurons in dehydration-induced renin secretion in conscious male rats. In addition, we expanded on our previous investigations of HA-induced renin secretion. Twenty-four hours of dehydration induced a 3-fold increase in plasma renin activity (PRA). Pretreatment with the HA synthesis inhibitor alpha-fluoromethylhistidine inhibited the dehydration-induced PRA secretion by 80% whereas pretreatment with the H1 receptor antagonist mepyramine (MEP) or the H2 receptor antagonist ranitidine (RAN) inhibited the PRA response to dehydration by approximately 40%. In euhydrated control rats, none of the HA-blocking agents had any significant effect on basal PRA secretion. Central administration of HA stimulated PRA almost 2-fold and the maximum concentration of PRA was reached after 15 min. Pretreatment with the H1 receptor antagonist MEP or the H2 receptor antagonist RAN totally inhibited the HA-induced PRA secretion. We conclude that HA activates renin secretion via H1 and H2 receptors and that HA seems to be a physiological mediator of dehydration-induced renin secretion via activation of H1 and H2 receptors. The effect is probably indirect and may among others involve the catecholaminergic and serotonergic systems.

Interactions of histaminergic and serotonergic neurons in the hypothalamic regulation of prolactin and ACTH secretion.

Serotonergic and histaminergic neuronal systems are both involved in mediation of the stress-induced release of the pituitary hormones prolactin (PRL) and ACTH. We investigated the possibility of an interaction between serotonin (5-HT) and histamine (HA) in regulation of PRL and ACTH secretion in conscious male rats. Animals were pretreated systemically with antagonists to 5-HT1, 5-HT2 or 5-HT3 receptors prior to intracerebroventricular (icv) administration of HA. The 5-HT1 + 2 receptor antagonist methysergide prevented and the 5-HT2 receptor antagonist LY 53857 attenuated the HA-induced PRL release while the 5-HT3 receptor antagonist ondansetron had no effect on this response. None of the three 5-HT receptor antagonists affected the ACTH response to HA. Specific blockade of HA synthesis by alpha-fluoromethylhistidine or blockade of postsynaptic HA receptors by icv infusion of the H1 receptor antagonist mepyramine or the H2 receptor antagonist cimetidine inhibited the PRL response to 5-HT or to the 5-HT precursor 5-hydroxytryptophan (5- HTP) given in combination with the 5-HT reuptake inhibitor fluoxetine (Flx). Blockade of the histaminergic system had no effect on the ACTH response to serotonergic stimulation. The H3 receptors are inhibitory HA receptors. Systemic pretreatment with the H3 receptor agonist R(alpha)methylhistamine, or the H3 receptor antagonist thioperamide had no effect on the hormone response to activation of the serotonergic system by 5-HTP plus Flx. We conclude that the serotonergic and histaminergic neuronal systems interact in their stimulation of PRL secretion, but not in their stimulation of ACTH secretion. This interaction involves serotonergic 5-HT1 and 5-HT2 receptors and histaminergic H1 and H2 receptors. Furthermore, the previously observed inhibitory effect of the H3 receptor agonist R(alpha)methylhistamine on stress-induced PRL and ACTH release seems not to be exerted by activation of presynaptic H3 receptors located on serotonergic neurons but rather on histaminergic neurons.

Dehydration stimulates hypothalamic gene expression of histamine synthesis enzyme: importance for neuroendocrine regulation of vasopressin and oxytocin secretion.

Dehydration associated with hyperosmolality and decreased extracellular volume stimulates arginine vasopressin (AVP) and oxytocin (OT) secretion from magnocellular neurons of the hypothalamus. The effects of hyperosmolality and decreased extracellular volume on the magnocellular neurons are mainly indirect and seem to be mediated centrally via several neurotransmitters and neuropeptides. Because histamine (HA), which serves as a central neurotransmitter, releases AVP and OT from the neurohypophysis when administered centrally, we investigated the possible role of HA in dehydration-induced AVP and OT secretion. To do this, we studied 1) the effect of dehydration on messenger RNA (mRNA) expression of the HA synthesis enzyme, histidine decarboxylase (HDC), in the tuberomammillary nucleus of the hypothalamus; and 2) the effect of HA synthesis inhibition during dehydration on AVP and OT mRNA expression in the supraoptic nucleus of the hypothalamus as well as on plasma AVP and OT levels. Forty-eight hours of dehydration increased the mRNA level of HDC in the tuberomammillary nuclei, whereas 24 h of dehydration had no effect. Pretreatment with the HA synthesis inhibitor alpha-fluoromethylhistidine (alpha FMH) increased the expression of HDC mRNA in 24-h dehydrated rats, but had no effect in euhydrated rats. In rats dehydrated for 48 h, the already increased level of HDC mRNA was not increased further by alpha FMH. Twenty-four and 48 h of dehydration increased AVP and OT mRNA levels in the supraoptic nucleus. This effect was inhibited by alpha FMH pretreatment. Dehydration increased the plasma levels of AVP and OT to an extent which depended on the duration of dehydration. Pretreatment with alpha FMH inhibited the hormone responses to 24 h of dehydration, but did not affect the responses to 48 h of dehydration. Twenty-four and 48 h of dehydration had no significant effect on the contents of AVP and OT in the neurohypophysis, whereas pretreatment with alpha FMH combined with 48 h of dehydration led to depletion of AVP stores in the neurohypophysis. Based on the present findings, we conclude that hypothalamic histaminergic neurons are involved in the regulation of dehydration-induced stimulation of magnocellular AVP and OT neurons.

Role of hypothalamic histaminergic neurons in mediation of ACTH and beta-endorphin responses to LPS endotoxin in vivo.

The involvement of hypothalamic histaminergic neurons in the mediation of the ACTH and beta-endorphin (beta-END) response to lipopolysaccharide (LPS) endotoxin was investigated in conscious male rats. LPS stimulated the release of ACTH and beta-END dose-dependently and increased the hypothalamic concentration of the histamine (HA) metabolite tele-methylhistamine significantly and that of HA slightly, indicating an increased turnover of neuronal HA. Pretreatment with the HA synthesis inhibitor alpha-fluoromethyl-histidine administered intracerebroventricularly (i.c.v.) or intraperitoneally (i.p.) inhibited the ACTH and beta-END response to LPS about 60%, whereas i.p. administration of the H3 receptor agonist R(alpha)methylHA, which inhibits HA synthesis and release, decreased the response about 50%. Pretreatment with the H1 receptor antagonist mepyramine (67 micrograms x 2 i.c.v.) inhibited the hormone response to LPS about 50%, while pretreatment with equimolar doses of the H2 receptor antagonists cimetidine (67 micrograms x 2 i.c.v.) or ranitidine (83 micrograms x 2 i.c.v.) had no effect on the LPS-induced release of ACTH and beta-END. When the H1 receptor antagonists mepyramine and cetirizine were administered i.p. in doses (10 mg/kg) which penetrate the blood-brain barrier the hormone response to LPS was inhibited 50% and 30%, respectively. Administered i.p. the H2 receptor antagonists had no effect on the hormone response to LPS. We conclude that hypothalamic histaminergic neurons in rats are involved in the mediation of the ACTH and beta-END response to LPS stimulation via activation of central postsynaptic H1 receptors.

Dehydration-induced release of vasopressin involves activation of hypothalamic histaminergic neurons.

The hypothalamic neurotransmitter histamine (HA) induces arginine vasopressin (AVP) release when administered centrally. We studied and characterized this effect of HA with respect to receptor involvement. In addition, we studied the possible role of hypothalamic histaminergic neurons in the mediation of a physiological stimulus (dehydration) for AVP secretion. Intracerebroventricular administration of HA, the H1-receptor agonists 2(3-bromophenyl)HA and 2-thiazolylethylamine, or the H2-receptor agonists amthamine or 4-methyl-HA stimulated AVP secretion. The stimulatory action of HA on AVP was inhibited by pretreatment with the H1-receptor antagonist mepyramine or the H2-receptor antagonist cimetidine. Twenty-four hours of dehydration elevated the plasma osmolality from 298 +/- 3 to 310 +/- 3 mmol/liter and increased the plasma AVP concentration 4-fold. The hypothalamic content of HA and its metabolite tele-methyl-HA was elevated in response to dehydration, indicating an increased synthesis and release of hypothalamic HA. Dehydration-induced AVP secretion was lowered when neuronal HA synthesis was inhibited by the administration of (S) alpha-fluoromethylhistidine or when the animals were pretreated with the H3-receptor agonist R(alpha)methylhistamine, which inhibits the release and synthesis of HA, the H1-receptor antagonists mepyramine and cetirizine, or the H2-receptor antagonists cimetidine and ranitidine. We conclude that HA, via activation of both H1- and H2-receptors, stimulates AVP release and that HA is a physiological regulator of AVP secretion.

Histamine stimulates c-fos expression in hypothalamic vasopressin-, oxytocin-, and corticotropin-releasing hormone-containing neurons.

The stimulatory action of centrally administered histamine (HA) on secretion of the anterior pituitary hormones ACTH, beta-endorphin, and PRL is indirect, and previous studies have suggested that hypothalamic neurons containing CRH, arginine vasopressin (AVP), and oxytocin (OT) are involved in this response. We studied the effect of HA on neuronal activation in the hypothalamus by investigating the expression of c-fos, which is a protooncogene activated early when neurons are stimulated. The expression of c-fos was evaluated by detection of c-fos immunoreactivity (c-fos-IR) using immunohistochemistry and by measurement of c-fos mRNA using in situ hybridization techniques. In addition, the identity of the HA-stimulated neurons was investigated by dual antigen immunohistochemistry visualizing AVP-, OT-, or CRH-IR in the neurons showing increased c-fos expression. HA (270 nmol) infused intracerebroventricularly increased c-fos-IR in the hypothalamus, especially in the periventricular hypothalamic areas and certain hypothalamic nuclei, including the paraventricular nucleus (PVN) and supraoptic nucleus (SON). c-fos-immunoreactive nuclei were observed throughout the SON, whereas in the PVN, c-fos-IR was particularly pronounced in the subnuclei known to contain AVP, OT, and CRH neurons. Double labeling experiments confirmed that c-fos was expressed in AVP-, OT-, and CRH-immunoreactive as well as other neurons. In addition, HA intracerebroventricularly induced a moderate expression of c-fos-IR in the arcuate nucleus. In situ hybridization showed increased levels of c-fos mRNA in both the PVN and SON after HA infusion. We conclude that HA-induced secretion of ACTH, beta-endorphin, and PRL may be mediated via activation of hypothalamic AVP, OT, and CRH neurons.

Impaired histamine- and stress-induced secretion of ACTH and beta-endorphin in vasopressin-deficient Brattleboro rats.

Arginine vasopressin (AVP), corticotropin-releasing hormone (CRH) and catecholamines seem to be involved in the histamine- (HA) and/or stress-induced release of the pro-opiomelanocortin-derived peptides adrenocorticotropic hormone (ACTH) and beta-endorphin (beta-END). The AVP component of the regulatory mechanism can be specifically studied in Brattleboro rats which lack AVP. These animals may therefore serve as a useful biological model for investigating the importance of AVP in the ACTH and beta-END response to HA and stress. On this background, we studied the ACTH and beta-END response to HA or restraint stress in conscious, male dizygotic AVP-deficient Brattleboro rats (DI) and compared the hypothalamic content of CRH and catecholamines in these rats with that of nondiabetic isogenic Long-Evans rats (LE). In addition, we studied the hypothalamic AVP content in LE rats after HA infusion or exposure to restraint stress. HA (270 nmol) administered intracerebroventricularly (i.c.v.) or 5 min of restraint stress caused a 6- to 7-fold increase in plasma concentrations of ACTH and beta-END in LE rats but only a 2- to 3-fold increase in DI rats (p < 0.01 vs. LE). The basal hypothalamic content of CRH and catecholamines (epinephrine, norepinephrine, and dopamine) was similar in DI and LE rats. The hypothalamic AVP content in LE rats was unaffected by central HA infusion or restraint stress and was undetectable in DI rats. We conclude that inherited lack of AVP impaired the ACTH and beta-END response to central HA administration as well as to restraint stress, suggesting that AVP is important for the mediation of these responses.

Insulin/hypoglycemia-induced adrenocorticotropin and beta-endorphin release: involvement of hypothalamic histaminergic neurons.

We have previously found that histamine (HA) is involved in the mediation of restraint- and ether stress-induced release of the POMC-derived peptides ACTH and beta-endorphin (beta-END). In the present study we investigated the possible involvement of hypothalamic histaminergic neurons in the mediation of insulin/hypoglycemia-induced release of ACTH and beta-END in conscious male rats. To do so, hypoglycemia stress was performed during 1) inhibition of HA synthesis, 2) activation of inhibitory presynaptic HA H3-auto-receptors, or 3) blockade of postsynaptic HA H1- or H2-receptors. Hypoglycemia (plasma glucose, 2.2 +/- 0.3 nmol) induced by insulin (3 IU/kg, ip) caused a 3- to 5-fold increase in the plasma concentrations of ACTH and beta-END. A negative exponential correlation was found between the plasma glucose concentration and the ACTH and beta-END levels. Pretreatment of the animals with the HA synthesis inhibitor alpha-fluoromethylhistidine (1.0 mumol) intracerebroventricularly (icv) in a lateral ventricle, inhibited the ACTH and beta-END responses to insulin/hypoglycemia by 60%. When administered ip (100 mumol/kg), the synthesis inhibitor decreased the beta-END response 50%, but did not affect ACTH secretion significantly. Pretreatment of the rats with the H3-receptor agonist R(alpha)methylhistamine (50 mumol/kg, ip, twice) inhibited the secretory responses of ACTH and beta-END to insulin/hypoglycemia by 60-80%. This inhibitory effect of R(alpha)methylhistamine was reversed by prior administration of the specific H3-receptor antagonist thioperamide. Administration of the H1-antagonists mepyramine and cetirizine dose-dependently inhibited the ACTH and beta-END responses to insulin/hypoglycemia, with the highest dose (mepyramine, 350 nmol, icv; cetirizine, 40 mumol/kg, ip) inhibiting the response by 80-100%. The H1-antagonist SKF-93944 (226 nmol, icv) inhibited the ACTH response, but had no effect on the beta-END response. Administration of the H2-antagonists cimetidine (400 nmol, icv) and ranitidine (400 nmol, icv) inhibited the ACTH and beta-END responses to insulin/hypoglycemia by 50-80%. We conclude that histaminergic neurons are involved in the mediation of the insulin/hypoglycemia-induced release of ACTH and beta-END and that the effect is mediated via activation of primarily postsynaptic H1-receptors and, to a lesser extent, H2-receptors.

Responses of anterior pituitary hormones and hypothalamic histamine to blockade of histamine synthesis and to selective activation or inactivation of presynaptic histamine H3 receptors in stressed rats.

The stress-induced release of anterior pituitary hormones and changes in hypothalamic content of histamine (HA) and its metabolite tele-methylHA (t-meHA) were studied in male rats during inhibition of HA synthesis or activation or blockade of HA H3 receptors. Pretreatment with the HA synthesis inhibitor alpha-fluoromethylhistidine (alpha-FMH; 200 micrograms intracerebroventricularly (icv) at -120 min) or the specific H3 receptor agonist R(alpha)methylhistamine (RmHA; 10 mg/kg intraperitoneally (ip) at -180 and -60 min) inhibited by 30-80% the responses of prolactin (PRL), corticotropin (ACTH) and beta-endorphin (beta-END) immunoreactivity to 1, 2.5 or 5 min of restraint stress (p < 0.05-0.01), but had no effect on basal secretion of the hormones. The inhibitory effect of the H3 receptor agonist RmHA (10 mg/kg x 2) on the hormone response to 5 min of restraint stress was prevented by simultaneous ip administration of the H3 receptor antagonist thioperamide. alpha-FMH reduced the hypothalamic content of HA 60% and that of t-meHA 30%, while RmHA had no effect on the HA content. Restraint stress for 5 min did not affect the HA and t-meHA contents, which may be due to the short duration of stress exposure. Pretreatment with the H3 receptor antagonist thioperamide (5 or 10 mg/kg ip at -120 min) had no effect on basal or restraint stress-induced release of PRL, ACTH or beta-END, although the compound increased the hypothalamic content of t-meHA 2-fold.(ABSTRACT TRUNCATED AT 250 WORDS)

Central activin administration modulates corticotropin-releasing hormone and adrenocorticotropin secretion.

A broad and diffuse neuronal network conveys information reflecting the state of the internal and external environment to the neurosecretory hypothalamus. Recently, we identified an inhibin-beta A- (I beta A) immunoreactive terminal field within the CRF-rich portion of the dorsomedial paraventricular nucleus which originates from a cell group in the commissural portion of the nucleus of the solitary tract (NTS). The NTS receives baroreceptor input, somatosensory input via the spinosolitary tract, and sensory information from the oral, thoracic, and abdominal cavities and, thus, is positioned to serve as a primary relay for visceral sensory inputs to neurons critical to the function of the hypothalamic-pituitary-adrenal (HPA) axis. Although these NTS cells contain multiple putative transmitters, we present evidence that activin, an inhibin-beta A dimer, plays a modulatory role in HPA axis function via facilitation of CRF release. First, intraventricular injection of activin-A (0-3 nmol), but not the related inhibin heterodimer, evoked dose-related 1.7- to 2.8-fold elevations of circulating ACTH levels in male rats. Second, analysis of hypophysial-portal plasma after bilateral paraventricular nucleus microinfusion of activin-A revealed a dose-related facilitation of CRF secretion up to 4-fold above preinjection levels which was unaccompanied by changes in arginine vasopressin levels. Finally, activin-A also enhanced CRF secretion from neonatal hypothalamic cells in primary culture with an EC50 dose of approximately 0.25 nM. Overall, these observations provide evidence of both an anatomical and a pharmacological substrate for activin-mediated central modulation of HPA axis function.