Angiotensin II reduces serotonin release in the rat subfornical organ area

Angiotensin II reduces serotonin release in the rat subfornical organ area

Peptides 24 (2003) 881–887 Angiotensin II reduces serotonin release in the rat subfornical organ area Junichi Tanaka a,b,∗ , Katsuhide Kariya c , Mas...

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Peptides 24 (2003) 881–887

Angiotensin II reduces serotonin release in the rat subfornical organ area Junichi Tanaka a,b,∗ , Katsuhide Kariya c , Masahiko Nomura d a

Department of Curriculum, Teaching and Memory, Naruto University of Education, Naruto, Tokushima 772-8502, Japan b Neuroscience Program, Naruto University of Education, Naruto, Tokushima 772-8502, Japan c Clinical Research Department, Pharmaceutical Division, Japan Tobacco Inc., Minato-ku, Tokyo 105-8422, Japan d Department of Physiology, Saitama Medical School, Moroyama-cho, Iruma-gun, Saitama 350-0495, Japan Received 14 March 2003; accepted 19 May 2003

Abstract In the present study we used intracerebral microdialysis techniques to examine whether angiotensin II (ANG II) modulates the release of serotonin (5-hydroxytryptamine, 5-HT) in the subfornical organ (SFO) in freely moving rats. Extracellular concentrations of 5-HT and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) in the region of the SFO were significantly decreased by microinjection of ANG II (10 pmol, 50 nl), but not by vehicle, into the dialysis site. No significant changes in the 5-HT and 5-HIAA levels caused by ANG II were observed in the sites away from the SFO. Water ingestion significantly enhanced the amount of the decrease in the 5-HT and 5-HIAA concentrations in the SFO area elicited by the ANG II injection. These results show that ANG II may reduce the release of 5-HT in the SFO area, and imply that the 5-HT receptor mechanism in the SFO area may participate in the elicitation of the drinking behavior to ANG II. © 2003 Elsevier Inc. All rights reserved. Keywords: Subfornical organ; Angiotensin II; 5-Hydroxytryptamine; 5-Hydroxyindoleacetic acid; Drinking

1. Introduction The subfornical organ (SFO), a forebrain circumventricular structure lacking a blood–brain barrier [26], is known to be the central site through which circulating and brain-derived angiotensin II (ANG II) acts to exert dipsogenic [9,11,12,20,21,27,33,35–39,42] and pressor [10,12,20–22] responses. The SFO is innervated by monoaminergic nerve terminals [6,13,17–19]. An immunohistochemical study has revealed that serotonergic axons within the SFO are derived from the dorsal raphe nucleus (DRN) [19]. With respect to the serotonergic projections to the SFO, previous studies have shown that nonhypotensive hypovolemia [16] or hemorrhage [40] enhances the release or turnover of serotonin (5-hydroxytryptamine, 5-HT) in the region of the SFO. Additionally, it has been reported that local administration of 5-HT into the SFO elicits enhanced thirst and elevated blood pressure [32]. These findings have led to the hypothesis that the serotonergic projections to the SFO may be involved in the modulation of the body fluid balance and cardiovascular function. ∗

Corresponding author. Tel.: +81-88-687-6277; fax: +81-88-687-6277. E-mail address: [email protected] (J. Tanaka).

0196-9781/$ – see front matter © 2003 Elsevier Inc. All rights reserved. doi:10.1016/S0196-9781(03)00164-5

It has been postulated that interactions between the angiotensinergic and serotonergic systems in the brain are important for the elicitation of drinking [3,7,14,24,25] and pressor [1,24,29] responses. The present study was carried out to examine whether ANG II acting at the SFO influences on the release of 5-HT in the SFO site using intracerebral microdialysis techniques. We examined the effects of microinjection of ANG II into the dialysis site on extracellular concentrations of 5-HT and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) in the SFO area. We also investigated the effects of water ingestion on the ANG II-induced changes in the 5-HT and 5-HIAA levels in the SFO area. 2. Methods The experiment was performed according to the guiding principles of the Physiological Society of Japan. 2.1. Animals Male Wistar rats (n = 44) weighing 260–330 g were used for the experiments. The animals were obtained from Nihon Charles River (Atsugi, Kanagawa, Japan). They were housed individually in hanging wire cages for at least 2 weeks before

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testing. Water and food were available ad libitum except where noted. Lights were on in the animal rooms for 12 h per day (light at 7:00–19:00 h), and temperature was maintained at 23–25 ◦ C. 2.2. Surgery The rats were anesthetized with sodium pentobarbital (60 mg/kg, i.p.) and placed in a stereotaxic frame. A microdialysis probe guide cannula (AG-12, Eicom Co., Kyoto, Japan) was lowered at a lateral angle of 15◦ to a coordinate which was 1 mm dorsal to the SFO since the probe assembly protrudes 1 mm below the ventral tip of the guide cannula when inserted. The guide cannula was then fixed to the skull with acrylic dental cement and small stainless steel screws.

II (Asp1 -Ile5 -ANG II) salt (Sigma Chemical Co., St. Louis, MO, USA) was dissolved in isotonic saline vehicle. In the previous study, we have demonstrated that microinjection of ANG II in a dose of 10 pmol elicits a robust drinking response [11,35,40]. In this study, injections of ANG II were thus administered in a dose of 10 pmol. Because it is crucial to minimize diffusion of injectate in neuroanatomic localization experiments, all injections of the drug solution or vehicle were given in a volume of 50 nl. The injections were achieved at a rate of 5 nl/s. In approximately half of the animals, the ANG II injection was performed under the condition that water is available for drinking. The testing was done at least within 3 h after the start of the light part of each rat’s light/dark cycle. The rat was then placed in the metabolism cage. Immediately following placement of the rat in the cage, the ANG II solution or vehicle was injected into the SFO.

2.3. Microdialysis 2.6. Histology A dialysis experiment was carried out 3 days after the implantation of the guide cannula. For microdialysis, a dialysis probe (MI-1-12-1, Eicom Co.) whose tip had 0.5-mm long semipermeable membrane (in vivo recovery at 2 ␮l/min is almost 25%), which consists of two lines for perfusion and of an injector needle for microinjection, was used. The dialysis probe was inserted into the implanted guide cannula. The probe was continuously perfused at a rate of 2 ␮l/min using a perfusion pump with a solution (NaCl 147 mM, CaCl2 2.3 mM, KCl 4 mM). All dialysates were thus collected at 20 min intervals. Three to 4 h after the beginning of the perfusion, stable basal 5-HT and 5-HIAA levels in the dialysates were obtained. Sample collections were continued 2 h after the injection of ANG II or vehicle.

At the termination of each experiment, the microdialysis probe was perfused with isotonic saline containing 2% Pontamine sky blue dye to verify the dialysis site by staining the structure. Each animal was then sacrificed with an overdose of sodium pentobarbital and perfused through the heart with isotonic saline to clear blood, which was followed by 10% formalin for fixation. The brain was removed and stored in the formalin saline before being cut on a freezing microtome at 50 ␮m in transverse sections. Sections were mounted on glass slides and stained with Neutral red for microscope examination. The stereotaxic coordinates for the sites of dialysis probes were determined according to the atlas of Paxinos and Watson [28].

2.4. Measurement of 5-HT and 5-HIAA

2.7. Data analysis

Immediately after collection, the dialysates were analyzed for concentrations of 5-HT and 5-HIAA, using HPLC (EP-10, Eicom Co.) with electrochemical detection (ECD-100, Eicom Co.). A mobile phase consisting of 0.1 M sodium acetate, 0.1 M citric acid, 0.75 mM sodium 1-octanesulfonate, 0.3 mM EDTA and 21% methanol (pH 3.9) was used to elute the monoamines from a reverse phase column (3.0 mm × 100 mm SC-3ODS column, Eicom Co.). The graphite working electrode was set at +750 mV versus a Ag/AgCl reference electrode and the flow rate was 0.5 ml/min.

All values are expressed as mean ± S.E.M. Data were analyzed by means of one-way or two-way repeated measures analysis of variance (ANOVA) and subsequent Tukey’s protected t-test. The criterion for significance was P < 0.05 in all cases.

2.5. Microinjection of ANG II Immediately before the start of the dialysis, the injector needle along the dialysis probe was filled with injectate and connected to a 5-␮l Hamilton gas chromatography syringe via approximately 1.0 m of polyethylene tubing. The tip of the injector needle was located at the midpoint of the membrane of the dialysis probe For intracerebral injection, ANG

3. Results 3.1. The probe placement Histological analysis from serial sections demonstrated that 26 out of 44 rats tested had probe placements in the region of the SFO and the remaining 18 rats had the placements in the sites away from the SFO (Fig. 1). Since a part of the probe was located within the SFO in all rats having the placements in the region of the SFO, the data from these animals were included in the analysis. The data from 18 animals having the placements in the sites away from the SFO were served and analyzed as a group.

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Table 1 Basal concentrations of 5-HT and 5-HIAA in the region of the SFO and the sites away from the SFO (pg/40 ␮l dialysate) Group

5-HT (n)

SFO-ANG II-Drinking SFO-ANG II SFO-Vehicle-Drinking SFO-Vehicle Vicinity-ANG II-Drinking Vicinity-ANG II Vicinity-Vehicle-Drinking Vicinity-Vehicle

6.8 8.1 8.3 7.2 2.7 3.1 2.6 –

± 0.8 (8) ± 1.0 (9) ± 1.3 (4) ± 1.1 (5) ± 0.7∗ (3) ± 0.5∗ (3) (1)

5-HIAA (n) 512.0 509.3 529.4 487.0 245.4 255.6 245.6 295.2

± ± ± ± ± ± ± ±

30.9 (8) 26.7 (9) 38.6 (4) 37.8 (5) 27.9∗ (6) 25.1∗ (5) 39.0∗ (4) 33.5∗ (3)

Values are shown as mean±S.E.M. 5-HT, 5-hydroxytryptamine; 5-HIAA, 5-hydroxyindoleacetic acid. Abbreviations for groups see text. ∗ P < 0.001 compared with the SFO-ANG II-Drinking, the SFO-ANG II, the SFO-Vehicle-Drinking, or the SFO-Vehicle group.

Fig. 1. The location of the dialysis probes. Oblique bars on schematic illustrations (8.10 and 7.60 mm anterior to the interaural line) depict the locations of the 0.5-mm long tip of the probe in the region of the subfornical organ (SFO, closed bars) and in the sites away from the SFO (open bars). SFO, subfornical organ; sm, stria medullaris of the thalamus; TS, triangular septal nucleus; vhc, ventral hippocampal commissure; 3V, third ventricle. Scale bar = 1 mm.

5-HT levels. On the other hand, the basal 5-HT concentrations in approximately two-thirds (n = 11) of the rats having the probe placements in the sites away from the SFO were below the detectable limit of the methods used in this study. The 5-HIAA concentrations from the dialysates could be detected in all the animals (n = 44) tested. The basal levels of 5-HIAA were significantly higher in the SFO area than in the sites away from of the SFO. No significant differences were observed between the groups of animals having similar probe placements in the basal 5-HIAA concentrations.

3.2. Basal concentrations of 5-HT and 5-HIAA Eight and nine out of 26 animals having the probe placements in the SFO area were utilized for the ANG II injection into the dialysis site under the condition that water is available (SFO-ANG II-Drinking group) and the condition that water is not available (SFO-ANG II group) for drinking, respectively. The remaining four and five rats were used for the saline treatment under the condition that water is available (SFO-Vehicle-Drinking group) and the condition that water is not available (SFO-Vehicle group) for drinking, respectively. Six and five out of 18 animals having the probe placements in the sites away from the SFO were used for the ANG II injection into the dialysis site under the condition that water is available (Vicinity-ANG II-Drinking group) and the condition that water is not available (Vicinity-ANG II group) for drinking, respectively. The remaining four and three rats were used for the vehicle treatment under the condition that water is available (Vicinity-Vehicle-Drinking group) and the condition that water is not available (Vicinity-Vehicle group) for drinking, respectively. The basal concentrations of 5-HT and 5-HIAA in each group are shown in Table 1. The differences in the dialysis probe placements reflected in the basal 5-HT and 5-HIAA concentrations. In all the animals (n = 26) having the probe placements in the SFO area, the basal 5-HT concentrations from the dialysates could be detected. There were no significant differences between the groups in the basal

3.3. Effects of ANG II injected into the dialysis site on dialysate 5-HT and 5-HIAA concentrations Changes in extracellular concentrations of 5-HT and 5-HIAA in the region of the SFO to ANG II are presented in Fig. 2A and B, respectively. In both the SFO-ANG II-Drinking (n = 8) and the SFO-ANG II (n = 9) groups, injections of ANG II elicited a significant decrease in either 5-HT or 5-HIAA concentrations in the SFO area. The amount of the decrease in either the 5-HT or 5-HIAA concentrations in the SFO area caused by the ANG II treatment was much greater in the condition that water is available for drinking. On the other hand, no significant changes in any of 5-HT and 5-HIAA concentrations were observed in both the SFO-Vehicle-Drinking (n = 4) and the SFO-Vehicle (n = 5) groups. Changes in extracellular 5-HT and 5-HIAA concentrations in the sites away from the SFO to ANG II are shown in Fig. 3A and B, respectively. In both the Vicinity-ANG II-Drinking (n = 3) and the Vicinity-ANG II (n = 3) groups, ANG II injected into the dialysis site did not cause a significant change in the 5-HT concentrations. The vehicle injection did not produce a remarkable alteration in the 5-HT concentration in one animal that was able to be detected the basal level (data not shown). No significant changes in the 5-HIAA concentrations were observed in any of the Vicinity-ANG II-Drinking (n = 6),

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Fig. 2. Changes in extracellular concentrations (expressed as percentage of the sample taken immediately before the microinjection; mean ± S.E.M.) of serotonin (5-hydroxytryptamine, 5-HT); (A) and its metabolite 5-hydroxyindoleacetic acid (5-HIAA); (B) in the region of the SFO and total water intake (C) after injections of angiotensin II (ANG II) or saline vehicle into the dialysis region of the SFO. (A and B) Open and closed circles indicate the alterations in the 5-HT (A) and 5-HIAA (B) concentrations in the SFO area caused by the ANG II injection under the condition that water is available (SFO-ANG II-Drinking group; n = 8) and the condition that water is not available (SFO-ANG II group; n = 9) for drinking, respectively. Open and closed triangles show the changes in the 5-HT (A) and 5-HIAA (B) levels in the SFO area caused by the vehicle injection under the condition that water is available (SFO-Vehicle-Drinking group; n = 4) and the condition that water is not available (SFO-Vehicle group; n = 5) for drinking, respectively. Injections of ANG II, but not vehicle, in the dialysis site significantly reduced the concentration of either 5-HT or 5-HIAA compared with the basal control level. ∗ P < 0.05, ∗∗ P < 0.01, ∗∗∗ P < 0.001 compared with the basal control level (0 min). ### P < 0.001 compared with those of the SFO-ANG II group. (C) The water intake (in each 20 min) in response to injections of ANG II (open histogram bars, n = 8) or saline vehicle (closed histogram bars, n = 4) into the dialysis site. Results are expressed as mean ± S.E.M. Injections of ANG II into the dialysis site elicited a robust drinking within 60 min after the injection. The vehicle injection did not cause any significant water intake. ### P < 0.001 compared with those of the vehicle injection.

the Vicinity-ANG II (n = 5), Vicinity-Vehicle-Drinking (n = 4), and Vicinity-Vehicle (n = 3) groups. 3.4. Effects of water ingestion on the ANG II-induced changes in the 5-HT and 5-HIAA concentrations Injections of ANG II into the SFO area caused robust drinking (n = 8; Fig. 2C). The total water intake in 120 min was 7.3 ± 1.2 ml (ranging 4.7–12.1 ml). The latency to onset of drinking was 29 ± 7 s. The vehicle injection into the SFO area, on the other hand, did not exhibit any significant water intake (total water volume in 120 min: 0.3 ± 0.2 ml; n = 4; Fig. 2C). Neither ANG II nor vehicle injected into the sites away from the SFO elicited significant water intake (total water volume in 120 min: 0.2 ± 0.1 ml for the ANG II injection, n = 6; 0.2 ± 0.1 ml for the vehicle injection, n = 4; Fig. 3C). To determine the statistical significance of the effects of the ANG II treatment and water intake in the animals having the probe placement in the SFO area, 4 × 8

two-way ANOVA was calculated with drug treatment as the between-group factor (four levels) and with time as the within-animal factor (eight levels). In the 5-HT concentrations in the SFO area, there were highly significant main effects of treatment (F(3, 22) = 40.271, P < 0.001) and time (F(7, 154) = 42.003, P < 0.001), and a significant interaction (F(21, 154) = 39.087, P < 0.001) in the overall ANOVA. In planned comparisons, both the SFO-ANG II-Drinking and the SFO-ANG II groups differed from the SFO-Vehicle-Drinking and the SFO-Vehicle groups at the 20 and 40 min periods (P < 0.001 for the 20 min period, P < 0.05 for the 40 min period). The SFO-ANG II-Drinking group also differed from the SFO-ANG II group at the 20 min periods (P < 0.001). In the 5-HIAA concentrations in the SFO area, there are also significant main effects of treatment (F(3, 22) = 47.369, P < 0.001) and time (F(7, 154) = 49.571, P < 0.001), and a significant interaction (F(21, 154) = 47.922, P < 0.001) in the overall ANOVA. In planned comparisons, both the SFO-ANG II-Drinking and the SFO-ANG

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Fig. 3. Changes in extracellular concentrations (expressed as percentage of the sample taken immediately before the microinjection; mean ± S.E.M.) of 5-HT and 5-HIAA in the sites away from the SFO after injections of ANG II or saline vehicle into the dialysis sites. (A and B) Open and closed circles indicate the changes in the 5-HT (A) and 5-HIAA (B) levels in the site away from the SFO in response to the ANG II injection under the condition that water is available (Vicinity-ANG II-Drinking group; n = 6) and the condition that water is not available (Vicinity-ANG II group; n = 5) for drinking, respectively. Open and closed triangles show the alterations in the 5-HIAA concentrations (B) in response to the vehicle injection under the condition that water is available (Vicinity-Vehicle-Drinking group; n = 4) and the condition that water is not available (Vicinity-Vehicle group; n = 3) for drinking, respectively. Neither ANG II nor vehicle injected into the dialysis region away from the SFO produced significant changes in the 5-HT and 5-HIAA levels. (C) The water intake (in each 20 min) in response to injections of ANG II (open histogram bars, n = 6) or saline vehicle (closed histogram bars, n = 4) into the sites away from the SFO. Results are expressed as mean ± S.E.M. Neither the ANG II nor the vehicle injection elicited a marked water intake within 120 min after the injection.

II groups differed from the SFO-Vehicle-Drinking and the SFO-Vehicle groups at the 20–60 min periods (P < 0.001 for the 20 and 40 min periods, P < 0.05 for the 60 min period). The SFO-ANG II-Drinking group also differed from the SFO-ANG II group at the 20 periods (P < 0.001).

4. Discussion The present study demonstrates that ANG II injected into the region of the SFO causes a reduction in the extracellular concentrations of 5-HT and 5-HIAA in the injection site. There are several possible mechanisms to explain the ANG II-induced attenuation of 5-HT release in the SFO area observed in this study. One explanation is that ANG II injected may act directly onto 5-HT terminals in the SFO area, which results in decreased 5-HT release. However, there are no previous data that ANG II receptors are located on 5-HT terminals. A related possibility is that activation of direct or indirect SFO efferent projections to the DRN in response to ANG II inhibits the activity of DRN neurons projecting to the SFO area. Indeed, SFO neurons send their fibers to the DRN [19] and these neurons are highly sensitive to ANG II [41]. Although further experiments are necessary, it is tempting to speculate that the neural network between the

SFO and the DRN may play an important role in the modulation of 5-HT release in the SFO area. A third possibility is that the decreased 5-HT release in the SFO area may be mediated through a baroreceptor reflex. An immunohistochemical tracing study has revealed that the DRN sends serotonergic fibers to the SFO area [19]. A previous investigation has reported that hypovolemia induced by subcutaneous treatment with polyethylene glycol enhances 5-HT turnover in the region of the SFO [16]. Electrophysiological and microdialysis observations have shown that hemorrhage activates DRN neurons projecting to the SFO and increases the release of 5-HT in the SFO area [40]. The DRN receives direct input from the parabrachial nucleus (PBN) and nucleus of the solitary tract [30], relay sites for cardiovascular information [15]. Previous reports have indicated that the 5-HT system in the brain is involved in the cardiovascular responses to ANG II [1,29]. These findings show the involvement of serotonergic projections from the DRN to the SFO in the control of cardiovascular functions, and offer the proposition that the DRN projections to the SFO may transmit information of the peripheral baroreceptors. It is well known that ANG II acting at the SFO induces hypertension [10,12,20–22]. Although no attempt was made in this study to measure arterial pressure, ANG II injected into the SFO area may raise arterial pressure. Thus, it might

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be expected that activation of the peripheral baroreceptors in response to an increase in arterial pressure elicited by the ANG II injection into the SFO area may serve to inhibit the activity of serotonergic DRN neurons projecting to the SFO, thereby causing reduced 5-HT release in the SFO area. Either blood-borne or brain-derived ANG II acting at the SFO causes drinking [9,11,12,20,21,27,33,35–38,42]. In this study, we found that water ingestion causes the larger reduction in the 5-HT release in the SFO which is caused by ANG II injected into the dialysis site. These results suggest the possibility that the 5-HT system in the SFO area may be involved in the water ingestion elicited by ANG II, and imply that DRN neurons projecting to the SFO area may receive neural inputs from several elements that are related to the sensation of body fluid volume and plasma osmolality. Previous studies have shown that activation of SFO neurons caused by ANG II produces drinking and pressor responses through their projections to several brain regions, such as the median preoptic nucleus [9,20,27,35,38,39] and the hypothalamic paraventricular nucleus [10,12,36,42]. Because of the two nuclei supply afferent projections to the DRN or the SFO [31,34], it is possible that the neural circuits between these nuclei may be implicated in the regulation of 5-HT release in the SFO area. Our data also lead to the hypothesis that the 5-HT system in the SFO area may modulate the elicitation of dipsogenic response caused by ANG II acting at the SFO. Indeed, it has been demonstrated that water and sodium intakes induced by ANG II injected intracerebroventricularly or into the SFO increase remarkably after pretreatment with bilateral injections of the 5-HT antagonist into the lateral PBN, indicating the involvement of the 5-HT mechanisms in the lateral PBN in the ANG II-induced water and sodium ingestion [7,24,25]. A review of the literature indicates that central serotonergic activation seems to exert a modulatory action on water consumption. In fact, 5-HT is present in prosencephalic and rhombencephalic structures implicated in the regulation of drinking behavior and blood pressure and central 5-HT seems to inhibit water ingestion in several circumstances [14]. Recent studies have shown that activation of several 5-HT receptor subtypes following injections of several 5-HT agonists into the third ventricle or several brain regions exerts an inhibitory effect on water intake, which is abolished or attenuated by pretreatment with their antagonists [2–4,7,8,23–25]. The present data raise the proposition that the SFO may be an action site of 5-HT for modulating the ANG II-induced water intake. If the 5-HT receptor mechanisms in the SFO area exert an inhibitory influence on water ingestion, it might be suggested that the decrease in the 5-HT release in the SFO area may result in the enhanced ANG II-induced thirst. On the other hand, there is a report showing that microinjection of 5-HT into the SFO causes drinking and pressor responses [32]. Since water was available ad libitum until the start of the dialysis, it seems likely that the body fluid balance might be kept. If the 5-HT system in the SFO serve to enhance thirst, it is possible to

speculate that the release of 5-HT release in the SFO area may be suppressed in order to prevent an excess of extracellular fluid volume. It is known that brain 5-HT circuits play a vital role under a condition that adaptative responses (i.e. arousal, vigilance, cognition, and alertness) are potentiated [5]. Since the ANG II-induced thirst under the condition that water is not available may produce a stress condition, it is suggested that the difference between the conditions with and without drinking in the 5-HT concentration in the SFO area may be partially attributable to the stress. The precise physiological roles of the 5-HT system in the SFO remain to be explained. In conclusion, the present microdialysis data provide the first evidence that ANG II serve to inhibit the release of 5-HT in the region of the SFO and the ANG II-induced reduction in the 5-HT release is diminished by water intake. Thus, it is suggested that the interactions between angiotensinergic and serotonergic mechanisms in the SFO area may play an important role in the regulation of the body fluid homeostasis. References [1] Benarroch EE, Pirola CJ, Alvarez AL, Nahmod VA. Serotonergic and noradrenergic mechanisms involved in the cardiovascular effects of angiotensin II injected into the anterior hypothalamic preoptic region of rats. Neuropharmacology 1981;20:9–13. [2] Castro L, Varjao B, Maldonado I, Campos I, Duque B, Fregoneze J, et al. Cebtral 5-HT3 receptors and water intake in rats. Physiol Behav 2002;77:349–59. [3] Castro L, De Castro-e-Silva E, Luz CP, Lima AKS, Souza F, Maldonado I. Central 5-HT4 receptors and drinking behavior. Pharmacol Biochem Behav 2002;66:443–8. [4] Castro L, Maldonado I, Campos I, Varjao B, Angelo AL, Athanazio RA, et al. Central administration of mCPP, a serotonin 5-HT2B/2C agonist, decreases water intake in rats. Pharmacol Bicochem Behav 2002;72:891–8. [5] Chrousos GP, Gold PW. The concepts of stress and stress system disorders: overview of physical and behavioral homeostasis. JAMA 1992;267:1244–52. [6] Ciriello J, Rosa-Arellani P, Solanor-Flores R. Direct projections to the subfornical organ from catecholaminergic neurons in the caudal nucleus of the solitary tract. Brain Res 1996;726:227–32. [7] Colombari DSA, Menani JV, Johnson AK. Forebrain angiotensin type 1 receptors and parabrachial serotonin in the control of NaCl and water intake. Am J Physiol 1996;271:R1470–6. [8] De Castro-e-Silva E, Sarmento C, Nascimento TA, Luz CP, Soares T, Marinho CA. Effect of third ventricle administration of L-692,247, a selective 5-HT1D receptor agonist, on water intake in rats. Pharmacol Biochem Behav 1997;57:749–54. [9] Eng R, Miselis RR. Polydipsia and abolition of angiotensin-induced drinking after transaction of subfornical organ efferent projections in the rat. Brain Res 1981;255:200–6. [10] Ferguson AV, Renaud LP. Hypothalamic paraventricular nucleus lesions decrease pressor responses to subfornical organ stimulation. Brain Res 1984;305:361–5. [11] Fujisawa S, Tanaka J, Nomura M. Estrogen attenuates the drinking response induced by activation of angiotensinergic pathways from the lateral hypothalamic area to the subfornical organ in female rats. Behav Brain Res 2001;122:33–41. [12] Gutman MB, Jones DL, Ciriello J. Effect of paraventricular nucleus lesions on drinking and pressor response to ANG II. Am J Physiol 1988;255:R882–7.

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