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Endocrinology Vol. 140, No. 8 3713-3719
Copyright © 1999 by The Endocrine Society

ARTICLES

Histaminergic and Catecholaminergic Interactions in the Central Regulation of Vasopressin and Oxytocin Secretion1

Ulrich Knigge, Edwin Willems, Andreas Kjær, Henrik Jørgensen and Jørgen Warberg

Department of Medical Physiology, Division of Endocrinology and Metabolism, The Panum Institute (U.K., E.W., A.K., H.J., J.W.) and Department of Surgery C, Rigshospitalet (U.K.), University of Copenhagen, Blegdamsvej 3 C, DK-2200 Copenhagen N, Denmark

Address all correspondence and requests for reprints to: Ulrich Knigge, M.D., Ph.D., Department of Medical Physiology, Building 12–3, The Panum Institute, University of Copenhagen, Blegdamsvej 3 C, DK-2200 Copenhagen N, Denmark. E-mail: Knigge{at}mfi.ku.dk


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
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 (icv), histamine (HA) as well as the H1 receptor agonist 2-thiazolylethylamine or the H2 receptor agonist 4-methylHA stimulated AVP and OT secretion. Prior icv infusion of antagonists specific to {alpha} or ß adrenergic receptors or their subtypes did not significantly affect the hormone response to HA or the histaminergic agonists. Infused icv norepinephrine (NE) or epinephrine (E) increased AVP and OT secretion. Prior icv 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.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
THE NEUROHYPOPHYSIAL hormones arginine vasopressin (AVP) and oxytocin (OT), which are released to the peripheral circulation by physiological stimuli including dehydration or hypovolemia and parturition or lactation, respectively (1, 2, 3), are primarily synthesized in perikarya in the supraoptic nucleus (SON) but also in perikarya located in magno- and parvocellular parts of the paraventricular nucleus (PVN) (4, 5).

It has previously been found that histamine (HA), which acts as a neurotransmitter in the hypothalamus (6, 7), increases plasma levels of AVP and OT (8, 9, 10, 11) and activates supraoptic—predominantly vasopressinergic—neurons (12, 13). Furthermore, we have reported that HA augments c-fos expression in AVP and OT neurons as well as messenger RNA (mRNA) for AVP and OT in the supraoptic and paraventricular nuclei (14, 15). A physiological role of neuronal HA in regulation of AVP and OT secretion has been evidenced by our recent findings that blockade of the histaminergic system inhibits the AVP response to dehydration in male rats and the OT response to suckling in lactating rats (14, 16). Both stimuli were found to increase mRNA expression of the HA synthesizing enzyme histidine decarboxylase in tuberomammillary nuclei of the hypothalamus (16, 17), where the histaminergic neurons exclusively originate (18, 19). Furthermore, dehydration was found to increase neuronal turnover of HA in the hypothalamus (14).

In addition to the participation of HA as well as other transmitters in the regulation of the neurohypophysial hormone secretion, it has been indicated that the catecholamines NE and E are involved in regulation of AVP and OT secretion as well (2, 3, 20).

Previous investigations have indicated that NE and E in general exert stimulatory effects on AVP secretion via {alpha}1 receptors, but in high doses may inhibit the AVP release via {alpha}2 and ß receptors (21, 22, 23, 24, 25). Similarly, both stimulatory and inhibitory effects of NE on OT secretion have been reported in relation to the suckling stimulus, depending on the type of adrenergic receptor affected (26). A stimulatory effect of NE on OT secretion has mostly been indicated by the finding that blockade of the noradrenergic system inhibits the OT response to stimuli such as suckling, stress, opioids, and cholecystokinin (20, 27, 28, 29).

Since both histaminergic neurons and noradrenergic neurons activate vasopressinergic and oxytocinergic neurons, increase the release of AVP and OT to the peripheral circulation, and seem to be involved in the mediation of the same physiological events that lead to the release of AVP or OT, we investigated the possibility of an interaction between the two aminergic neuronal systems in conscious male rats.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Animals
Male rats of the Wistar strain (275–325 g) bred at the Panum Institute were housed under controlled conditions of temperature (22 ± 1 C), humidity (40–50%) and lighting (lights on 0600–1800 h daily). The rats had free access to laboratory chow and tap water. The well being of the animals were secured in concordance with Danish national rules set forth by the Ministry of Justice.

Compounds
The following histaminergic compounds were used: Histamine 2HCl (HA; purchased from Sigma Chemical Co., St. Louis, MO), the H1 receptor agonist 2-thiazolylethylamine 2HCl (2-TEA; gift from SmithKline Beecham, Welwyn Garden City, UK), the H2 receptor agonist 4-methylHA 2HCl (4-meHA; gift from SmithKline Beecham), the H3 receptor agonist imetit 2HBr (Ime; gift from professor H. Timmerman, Free University, Amsterdam, The Netherlands), the H1 receptor antagonist mepyramine maleate (Mep; gift from DAK, Copenhagen, Denmark), and the H2 receptor antagonist cimetidine 2HCl (Cim; gift from GEA, Copenhagen, Denmark). The doses of Mep, Cim, or Ime have previously been found to inhibit the AVP or responses to HA, dehydration or suckling (14, 16, 30, 31).

The following catecholaminergic compounds were used: the {alpha} + ß receptor agonist epinephrine bitratrate (E), the {alpha} + ß1 receptor agonist norepinephrine bitratrate (NE), the {alpha}1 + 2 receptor antagonists phenoxybenzamine HCl (Phb) and phentolamine mesylate (Pht), the {alpha}1 receptor antagonist prazocin Hcl (Pra), the {alpha}2 receptor antagonist yohimbine HCl (Yoh), the ß1 + 2 receptor antagonist propranolol HCl (Pro), the ß1 receptor antagonist atenolol HCl (Ate), and the ß2 receptor antagonist ICI-118,551 (ICI). The adrenergic agonists and antagonists were purchased from Research Biochemical International (Natick, MA). The adrenergic antagonists were administered in a dose of 1 mmol as some of the antagonists in that dose have been found to inhibit the AVP or OT responses to catecholamines, suckling or stress (20, 21, 22, 23, 24, 25, 27, 28, 29). All compounds were dissolved in saline except Pra and Cim, which were dissolved in saline acidified with 0.1 N HCl and adjusted with 0.1 N NaOH to pH 7.4, and were administered intracerebroventricularly (icv). However, Ime was injected ip as the compound by this administration route has been found to inhibit stress-induced release of pituitary hormones (32).

Experimental procedures
Approximately 1 week before experimentation, a permanent cannula was implanted in a lateral ventricle of the brain during pentobarbital anesthesia (60 mg/kg ip) as previously described (33). The tip of the cannula was positioned according to the following coordinates: 1.5 mm lateral from the bregma on the coronal suture of the skull, 4.5 mm below the surface of the skull (34). At the day of the experiment, the cannula was extended by SILASTIC brand silicon tubing (Polystan, Copenhagen, Denmark) filled with solutions (5 µl) of saline and/or the compounds studied. This permitted icv infusion of test substances (2 µl/min) without disturbing the rats. All experiments were performed between 1000 and 1400 h after the rats had adapted in the laboratory for at least 90 min in individual cages.

The time points chosen for administration of compounds were based on previous experiments demonstrating significant effects of receptor agonists and antagonists on AVP or OT secretion (10, 14, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30).

Exp 1: Effect of adrenergic {alpha} or ß receptor antagonists on HA-, 2-TEA- or 4-meHA-stimulated AVP and OT secretion
Saline or the adrenergic receptor antagonists in a dose of 1 mmol was infused icv at time -20 min followed by icv infusion at -15 min of saline, HA, 2-TEA or 4-meHA in a dose of 270, 2180, or 790 nmol, respectively. The two histaminergic agonists were administered in molar doses estimated to exert equal effect with HA at the respective receptors (35). The animals were decapitated at 0 min and blood was collected from the trunk. The number of animals in each group ranged from 8–13.

Exp 2: Effect of H1 or H2 receptor antagonists or an H3 receptor agonist on E- or NE-stimulated AVP and OT secretion
Saline or the H1 receptor antagonist Mep or the H2 receptor antagonist Cim was infused icv at time -20 min in a dose of 350 nmol or 400 nmol, respectively, followed by icv infusion at -15 min of saline, E or NE in an dose of 25 nmol. In other experiments saline or the H3 receptor agonists Ime in a dose of 2 mg/kg rat was administered ip in a volume of 1 ml at time -180 min followed at -15 min by icv infusion of saline, E or NE in an dose of 5 mmol. The animals were decapitated at 0 min and blood collected from the trunk. The number of animals in each group ranged from 7–12.

Exp 3: Effect of HA, E-, or NE on mean arterial blood pressure
In a group of rats the left carotid artery was cannulated by a pp50 SILASTIC brand tubing for measurement of blood pressure. The catheter was inserted during pentobarbital anesthesia (60 mg/kg ip) 2 days before experimentation. At the day of experimentation, the catheter was connected to a Gould-Statham P50 pressure transducer and via a custom built amplifier the artery blood pressure signals were continuously recorded by a Watanabe Mark IV four channel hot stylus recorder adjusted to a speed of 10 mm/min. After calibration of the system followed by an equilibration period of 30 min, the blood pressure measurement was started. Saline, HA (270 nmol), E or NE (25 nmol) was infused icv 5 min later starting at 0 min (5 µl; 2 µl/min), and blood pressure was recorded until 20 min after administration of the amines or saline. The changes in mean arterial blood pressure ({Delta}-MABP) from time 0 min were determined from the curves at 0, 1, 2, 5, 10, 15, and 20 min.

Analysis of AVP and OT
Blood was collected in polyethylene tubes containing 100 µl of 0.5 M EDTA and 50 µl of aprotinin (Trasylol 20.000 KIU/ml; Bayer, Leverkusen, Germany). The blood samples were centrifuged at 4 C, and plasma was stored at -20 C until analyzed for AVP and OT by specific radioimmunoassays (16, 36).

In brief, AVP and OT were measured in plasma extracted by means of C18 Sep-Pak cartridges (Waters Corp., Milford, MA) using specific antisera (abAVP 1406 and abOT 90173), which were raised in rabbits immunized with AVP or OT coupled to thyroglobulin. The abAVP was used in a final dilution of 1:325,000 and the antiserum cross-reacted 100% with lysine vasopressin and 0.0003% with OT, but did not cross-react with arginine vasotocin, angiotensin-II or 1-deamino-8-D-arginine vasopressin. Synthetic AVP (mol wt: 1,083; Penisula Laboratories Inc., Belmont, CA) served as reference preparation. Iodinated AVP ([125I]AVP) was purchased from Amersham Pharmacia Biotech (Aylesbury, UK). The abOT was used in a final dilution of 1:26,000 and the antiserum cross-reacted 100% with vasotocin and 0.2% with CRH but did not cross-react with AVP, PRL, ACTH, ß-END, or angiotensin II. Synthetic OT (mol wt: 1,006; Peninsula Laboratories, Inc.) served as reference preparation. Iodinated OT (125I-OT) was purchased from NEN Life Science Products (Wilmington, DE).

For the AVP and OT assays, the least detectable quantity was 0.1–0.3 pmol/liter plasma and 4–6 pmol/liter plasma, respectively. For both assays, the intra and interassay coefficients of variations were 8% and 12%.

Statistical procedures
Results are presented as the mean ± SEM and evaluated by one-way ANOVA, followed by Duncan’s test for multiple comparisons when appropriate. The limit of significance was P < 0.05.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Exp 1: Effect of adrenergic {alpha} or ß receptor antagonists on HA-, 2-TEA-, or 4-meHA-stimulated AVP and OT secretion
HA stimulated AVP and OT secretion almost 4- and 6-fold, respectively (P < 0.01; Fig. 1Go, A and B). Prior administration of the nonselective or selective {alpha} receptor antagonists had no effect on HA-stimulated AVP and OT secretion, whereas the ß1 + 2 receptor antagonist Pro reduced the AVP and OT response 70% and 40%, respectively (Fig. 1Go, A and B). This effect of Pro was not significant. None of the selective ß receptor antagonists affected the hormone response to HA (Fig. 1Go, A and B).



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  		Figure 1. Effect of the adrenergic receptor antagonists Phb ({alpha}1 + 2), Pht ({alpha}1 + 2), Pra ({alpha}1), Yoh ({alpha}2), Pro (ß1 + 2), Ate (ß1), or ICI (ß2) on HA stimulated release of AVP (A) or OT (B). The adrenergic receptor antagonists (1 mmol) or saline were administered icv at -20 min and HA (270 nmol) was infused icv at -15 min. The animals were decapitated at 0 min. The data represent the mean ± SEM of 8–13 rats in each group. ##, P < 0.01 vs. Control.

 
To evaluate the inhibitory action of Pro on HA-induced hormone release, the effect on AVP and OT secretion of specific H1 (2-TEA) and H2 (4-meHA) receptor agonists was studied. The H1 and H2 receptor agonist stimulated AVP secretion 15- and 7-fold, respectively and OT secretion 9- and 10-fold, respectively (Fig. 2Go, A and B). However, none of the adrenergic receptor antagonists studied, including Pro, affected these responses (Fig. 2Go, A and B). None of the {alpha} or ß receptor antagonists affected basal secretion of AVP or OT significantly (Table 1Go).



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  		Figure 2. Effect of the adrenergic receptor antagonists Phb ({alpha}1 + 2), Pht ({alpha}1 + 2), or Pro (ß1 + 2) on 2-TEA (H1 receptor agonist) or 4-MeHA (H2 receptor agonist) stimulated release of AVP (A) or OT (B). Further details are given in legend to Fig. 1Go. The data represent the mean ± SEM of 8–10 rats in each group. ##, P < 0.01 vs. Control.

 

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  		Table 1. Effect of the adrenergic receptor antagonists Phb ({alpha}1 + 2), Pht ({alpha}1 + 2), Pra ({alpha}1), Yoh ({alpha}2), Pro (ß1 + 2), Ate (ß1) or ICI (ß2) on basal secretion of AVP and OT

 
Exp 2: Effect of H1 or H2 receptor antagonists or an H3 receptor agonist on E- or NE-stimulated AVP and OT secretion
The H1- or H2 receptor antagonists Mep or Cim or the H3 receptor agonist Ime had no effect on basal AVP and OT secretion (Table 2Go).


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  		Table 2. Effect of the H1 receptor antagonist Mep, the H2 receptor antagonist Cim or the H3 receptor agonist Ime on basal secretion of AVP and OT

 
Infused icv NE stimulated AVP and OT secretion about 5-fold (P < 0.01; Fig. 3Go, A and B). Intracerebroventricular pretreatment with the H1 receptor antagonist Mep almost abolished (P < 0.01), whereas the H2 receptor antagonist Cim or the H3 receptor agonist Ime inhibited by almost 60% the AVP response to NE (P < 0.05; Fig. 3AGo). The OT response to NE was inhibited 70% by Mep (P < 0.01) and about 50% by Cim or Ime (P < 0.05; Fig. 3BGo).



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  		Figure 3. Effect of the H1 receptor antagonist Mep, the H2 receptor antagonist Cim or the H3 receptor agonist Ime on NE-induced release of AVP (A) or OT (B). Ime (2 mg/kg rat) was injected ip at -180 min and Mep (350 nmol), Cim (400 nmol) were administered icv at -20 min and NE (25 nmol) was infused icv at -15 min. Data from control rats administered with saline icv at -20 min or ip at -180 min were pooled. The animals were decapitated at 0 min. The data represent the mean ± SEM of 7–10 rats in each group. ##, P < 0.01 vs. Control; *, P < 0.05 vs. Sa + NE; **, P < 0.01 vs. Sa + NE.

 
Administered icv E increased plasma AVP and OT 12- and 9-fold, respectively (P < 0.01; Fig. 4Go, A and B). Pretreatment with the H1 receptor antagonist Mep inhibited the AVP response more than 60% (P < 0.01; Fig. 4AGo) but the OT response only 20% (NS; Fig. 4BGo). The H2 receptor antagonist Cim decreased the AVP and OT responses 60% and 40%, respectively (P < 0.05; Fig. 4Go, A and B). Administered ip the H3 receptor agonist Ime reduced the AVP response about 50% (P < 0.05; Fig. 4AGo) and the OT response 40% (P < 0.05; Fig. 4BGo).



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  		Figure 4. Effect of the H1 receptor antagonist Mep, the H2 receptor antagonist Cim or the H3 receptor agonist Ime on E-induced release of AVP (A) or OT (B). Further details are given in legend to Fig. 3Go. The data represent the mean ± SEM of 7–10 rats in each group. ##, P < 0.01 vs. Control; *, P < 0.05 vs. Sa + E; **, P < 0.01 vs. Sa + E.

 
Exp 3: Effect of HA, E-, or NE on mean arterial blood pressure
HA had no effect on MABP, while NE caused an initial increase of approximately 10% at 1 and 2.5 min (P < 0.01). MABP returned to basal level within 10 min (Fig. 5Go). E slightly but not significantly increased MABP within the first minute (Fig. 5Go).



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  		Figure 5. Change in mean arterial blood pressure ({Delta}-MABP) from 0 min after icv infusion of saline, HA, NE, or E in conscious male rats. Further details are given in the text. The data represent the mean ± SEM of 8–10 rats in each group. ##, P < 0.01 vs. saline at 1 and 2.5 min.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
We found that central administration of the amines HA, 2-TEA, 4-meHA, NE, and E stimulated the secretion of the neurohypophysial hormones AVP and OT in conscious male rats. The present findings confirm previous observations in relation to HA and NE (8, 9, 11, 14, 21, 22, 23, 24, 25, 37, 38), but to our knowledge it is the first presentation of a stimulatory effect of centrally administered E on plasma OT levels in vivo.

The stimulatory effect of HA, the H1 receptor agonist 2-TEA, and the H2 receptor agonist 4-meHA on AVP secretion is in accordance with previous observations that the compounds increase plasma AVP and that HA excites vasopressinergic neurons (13, 14, 38, 39, 40). However, differences have been obtained concerning the effect of HA on OT. Thus, we have previously (8) and presently found that central administration of HA, 2-TEA and 4-meHA increase plasma OT, while it has been reported that electrical activation of histaminergic neurons in the tuberomammillary nucleus evoked inhibitory postsynaptic potentials in oxytocinergic neurons mediated via H2 receptors (40). That HA exerts both stimulatory and inhibitory effects on OT neurons has been suggested because HA depolarized and hyperpolarized or had no effect on oxytocinergic neurons in the SON 39). However, the resulting effect of HA administered icv seems to be stimulatory as HA increases plasma OT.

The H1 or H2 receptor agonists stimulated AVP and OT secretion significantly more than did HA. We have previously observed that similar doses of these two agonists and of other H1 and H2 receptors agonists increased plasma AVP and OT concentration to a level higher than that achieved by HA in the present dose (8, 14). The higher AVP and OT response to the H1 or H2 receptor agonist compared with that of HA seems to be unrelated to the compounds affinity for H1 or H2 receptors (35). Moreover, the H1 and H2 receptor agonists were administered in doses that were calculated to be equipotent to that of HA (35) and that increase plasma ACTH concentration to a level identical to that obtained by HA (41). These findings as well as the almost identical chemical structure of the agonists and HA (35) may also exclude that the different stimulatory effect was caused by differences in T1/2 of the compounds. The T1/2 of HA in the brain has previously been found to be short (6, 7). One explanation might be that HA in contrast to the H1 and H2 receptor agonists also activates presynaptic H3 receptors (6). In accordance with this, activation of H3 receptors by R({alpha})mehtylHA inhibits the stimulated release of AVP and OT (31). Thus, HA by concomitant activation of postsynaptic H1 and H2 receptors—thereby stimulating AVP and OT secretion—may at the same time inhibit these responses by activation of presynaptic H3 receptors.

It has previously been reported that blockade of {alpha}1 receptors inhibited the AVP response to NE in male rats and the OT response to suckling in lactating rats, and it has been suggested that the catecholaminergic activation of AVP and OT neurons in the SON and PVN is mediated via {alpha}1 receptors and may be inhibited via {alpha}2 and ß receptors (20, 21, 22, 23, 24, 25, 26). However, in the present study blockade of central {alpha} or ß receptors or their receptor subtypes by specific adrenergic receptor antagonists did not affect the HA-induced response of AVP and OT. The use of an insufficient dose (1 mmol) is unlikely to explain the lack of effect of the adrenergic receptor antagonists, because several of the antagonists in almost equivalent doses have been found to inhibit the AVP or OT responses to catecholamines, suckling or stress (20, 21, 22, 23, 24, 25, 27, 28, 29). We have recently found that the {alpha}1 or the {alpha}1 + 2 receptor antagonists Pra, Phb, and Pht in dose identical to that used in this study inhibited or even prevented the PRL response to HA (42). The nonselective ß receptor antagonist Pro reduced the AVP and OT response to HA. However, this effect was not significant when all groups were analyzed in the same ANOVA, and the hormone response to HA was not affected by administration of selective ß1 or ß2 receptor antagonists. Furthermore, the AVP and OT responses to the histaminergic agonists were not affected by Pro or other adrenergic agonists. Based on the present experiments, it is likely that the histaminergic system stimulates the neurohypophysial hormones AVP and OT independently of noradrenergic or adrenergic neurons. This result is different from the finding, that increase in MABP induced by infusion of HA in the PVN was abolished by simultaneous administration of {alpha}1 but not {alpha}2 or ß receptor antagonists (43). However, in the present study the dose of HA used did not affect mean arterial blood pressure.

In contrast to lack of effect of adrenergic receptor antagonists on the stimulatory action of HA, we found that specific blockade of postsynaptic H1 or H2 receptors by Mep or Cim, respectively, inhibited the AVP and OT responses to stimulation of catecholaminergic {alpha} and ß receptors in the brain induced by central administration of NE or E. Only Mep had no significant effect on the OT response to E, although the response was reduced and Mep significantly inhibited the AVP response. It is possible that H1 receptors are differently involved in the catecholamine-induced release of AVP and OT, although we believe it is more likely that the finding is a Type II error, which we calculated to be approximately 25%. The general inhibitory effect of the H1 and H2 receptor antagonists on catecholamine-induced secretion of neurohypophysial hormones was substantiated by the finding that inhibition of endogenous neuronal HA release or synthesis caused by activation of presynaptic H3 receptors by the agonist Ime significantly reduced the AVP or OT responses to NE and E. The effect of the histaminergic compounds were not due to an antagonist affect on adrenergic receptors because the three compounds possess very low affinity for these receptors (35). The findings indicate that blockade of the neuronal histaminergic system reduces the capability of the neuronal catecholaminergic systems to stimulate AVP and OT secretion. The minor or no effect of NE and E on MABP suggest that catecholamine-induced changes in blood pressure do not interfere with the results obtained.

The finding that the postsynaptic H1 or H2 receptor antagonists Mep or Cim, as well as the presynaptic H3 receptor agonist Ime, inhibited the catecholamine-induced AVP and OT release is in accordance with and supported by our previous findings. We found that blockade of H1 or H2 receptors as well as blockade of HA release or synthesis induced by H3 receptor agonists or {alpha}-fluromethylhistidine, which inhibits the HA synthesizing enzyme histidine decarboxylase, decreased the AVP response to central administration of HA or dehydration (14, 31) and the OT response to HA, dehydration or suckling (16, 30, 31). Thus, the present results further substantiate the important role of histaminergic neurons in the central regulation of AVP and OT secretion. Furthermore, the studies indicate that the effect of the histaminergic system occurs via activation of postsynaptic H1 and H2 receptors. However, other studies have suggested that the effect of HA on vasopressinergic neurons in the SON occurs via activation of H1 receptors only (11, 13, 44, 45). The difference between these primarily electrophysiological studies and our studies concerning the postsynaptic receptors involved in the mediation of the response may be due to differences in the measurement of magnocellular activity, i.e. electrical recordings from neurons in vitro vs. measurement of peripheral hormone release by RIA in vivo. Thus, the results obtained from the in vitro studies may not reflect what occurs in the intact animal. Furthermore, in the aspect of HA, the physiological relevance of electrical recordings from single neurons has been questioned (6). The possibility that the inhibitory effect of the H2 receptor antagonists and stimulatory effect of the H2 receptor agonists found in our studies are caused by a nonspecific effect of the compounds on H1 receptors seems unlikely, because the same effect was found by all the compounds used, even by very specific agonists (8, 14).

The present study does not clarify the site(s) of action in the brain where the interaction between the histaminergic and noradrenergic/adrenergic system occurs. However, other investigations may to some extent reveal these site(s). The histaminergic neurons originate exclusively in the tuberomammillary nuclei of the posterior hypothalamus and projects to other brain areas as well as to other hypothalamic areas including the SON and the PVN (12, 18, 19). Therefore, it is possible that NE and E activate histaminergic perikarya in the posterior hypothalamus, which subsequently activates vasopressinergic and oxytocinergic neurons in the SON and PVN. The stimulatory effect of NE or E may then be reduced by inhibition of HA synthesis or release by the H3 receptor agonist Ime or by blockade of postsynaptic H1 and H2 receptors. However, such a mediating effect of HA seems unlikely because injection of NE into the posterior hypothalamus, where the histaminergic perikarya are located, had no effect on AVP secretion (21).

It is more likely that the interaction between the two aminergic systems occurs in the SON and PVN. Histaminergic nerve fibers densely innervate the SON and PVN making contact to magnocellular neurons (12, 18, 19), and administration of the H3 receptor antagonist thioperamide, which enhances neuronal HA release, increased mRNA expression and immunoreactivity of c-fos in magnocellular neurons in the SON and PVN (46). Furthermore, autoradiographic studies have revealed that in the SON and PVN H1 receptors are abundant and the density of H3 receptors is moderate, whereas H2 receptors are found in lower density (47, 48, 49, 50, 51). Noradrenergic and adrenergic neurons project from the brain stem to the SON and the PVN (52), where they are in contact with vasopressinergic and oxytocinergic neurons (1, 53, 54). Therefore, it is likely that histaminergic and catecholaminergic neurons make contacts on identical magnocellular neurons in the SON and PVN and that an intact histaminergic system is required before catecholaminergic receptor activation induces a complete stimulation of AVP and OT neurons. In contrast, the lack of effect of the adrenergic receptor antagonists on HA-stimulated AVP and OT secretion suggest that the presence of activated catecholaminergic receptors are not a prerequisite for histaminergic stimulation of the neurohypophysial hormones. The present findings further substantiate an important role of histaminergic neurons in the central regulation of AVP and OT secretion.


   Acknowledgments
 
We thank Elsa Larsen and Jytte Oxbøl for skilled technical assistance.


   Footnotes
 
1 This study was supported by grants from the Danish Medical Research Council; Ib Henriksen’s Foundation; the Velux Foundation; Jacob and Olga Madsen’s Foundation; P. Carl Petersen’s Foundation; the Danish Hospital Foundation for Medical Research, Regions of Copenhagen, the Faroe Islands and Greenland; The Lundbeck Foundation; the NOVO-Nordisk Foundation; Poul M. and Birthe Christiansen’s Foundation; Gerda and Aage Haensch’s Foundation; and the Foundation for the Advancement of Medical Research. Part of the study was supported by the Commission of the European Communities (contract: CEE BMH1-CT 92–1087). Back

Received December 23, 1998.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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  3. Crowley WR, Armstrong WE 1992 Neurochemical regulation of oxytocin secretion in lactation. Endocr Rev 13:33–65[CrossRef][Medline]
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