Elsevier

Brain Research

Volume 1028, Issue 1, 26 November 2004, Pages 48-58
Brain Research

Research report
Role of central 5-HT3 receptors in the control of blood pressure in stressed and non-stressed rats

https://doi.org/10.1016/j.brainres.2004.08.063Get rights and content

Abstract

The aim of the present study was to investigate the participation of central 5-HT3 receptors in the control of blood pressure and heart rate (HR) of non-stressed and stressed rats. The pharmacological stimulation of brain 5-HT3 receptors by third ventricle injections of the selective 5-HT3 receptor agonist m-CPBG induced a significant decrease in blood pressure in non-stressed rats and impaired the hypertensive response induced by restraint stress. The blockade of brain 5-HT3 receptors by the central administration of the selective 5-HT3 antagonist ondansetron elicited a significant increase in blood pressure in non-stressed rats. Conversely, the hypertensive response induced by restraint stress was not affected by central administration of ondansetron. Additionally, baroreflex-mediated bradycardia during phenylephrine-induced hypertensive response was preserved in non-stressed animals receiving third ventricle injections of m-CPBG, while the baroreflex-mediated tachycardia that occurs during the hypotensive response induced by the administration of sodium nitroprusside was impaired. It is concluded that the serotoninergic component represented by the brain 5-HT3 receptors exerts a tonic inhibitory influence on the central control of blood pressure in non-stressed rats, probably by a sympathoinhibitory-related mechanism. On the other hand, during stress, this central 5-HT3-dependent inhibitory drive is overwhelmed by the different neurochemical systems that harmonically trigger and sustain the hypertensive response.

Introduction

Central serotonin pathways comprise a complex system of mesencephalic origin that spread to different brain areas and operate through a protean array of biochemical processes triggered by serotonin actions on several membrane receptors [2]. Many brain areas involved in cardiovascular regulation are innervated by serotonin pathways, and brain serotonin may play important roles in the central nervous system's control of cardiovascular function [27]. However, a comprehensive picture of brain serotonin actions on the cardiovascular system has not yet been achieved.

Data available in the literature show that distinct central serotonin receptors (5-HT1A, 5-HT2 and 5-HT3) are involved in the control of cardiovascular function [13], [27]. However, the way in which brain serotonin pathways and receptors regulate cardiovascular function has not yet been clarified. It seems that the activation of distinct brain serotonin receptors and central serotoninergic areas may exert conflicting responses on blood pressure and heart rate (HR) [27], [35]. Data obtained from the literature on the central control of blood pressure portray a rather confusing picture. Central serotonin stimulation may promote sympathoexcitatory or inhibitory effects, increasing or decreasing blood pressure. Indeed, activation of brain 5-HT1A receptors located primarily in the midbrain raphe and brainstem nuclei generates hypotension and bradycardia that seem to depend on a reduced sympathetic activity and an increase in vagal tone [25], while the activation of these same receptors located in forebrain structures produces the opposite result [34]. In rats, the activation of 5-HT2 receptors in the lateral hypothalamus induces an increase in blood pressure and HR [23], an effect that is also obtained by the pharmacological stimulation of 5-HT2 receptors located within the paraventricular nucleus [3]. On the other hand, a hypotensive and bradycardic response is observed when 5-HT2 receptors in the nucleus of solitary tract (NTS) are stimulated [37]. Knowledge regarding the roles played by the other brain serotonin receptor subtypes in the control of cardiovascular function is practically negligible [27], [41].

Many brain areas controlling cardiovascular function also regulate physiological and behavioral responses linked to body fluid homeostasis. Circumventricular structures at sites both in the forebrain and in the hindbrain participate in the control of several parameters such as water and salt intake and renal water and electrolyte excretion, whose final concerted adjustments enable blood volume, blood pressure and plasma osmolarity to be maintained within their narrow physiological range [10], [21].

We have recently demonstrated that central serotonin receptors play a significant role in the control of ingestive behaviors associated with body fluid homeostasis. In fact, previous studies from our laboratory have shown that stimulation of central 5-HT2B/2C and 5-HT3 receptors decreases salt intake in sodium-depleted rats [7] and the specific activation of these same receptors reduces water intake induced by several physiological and pharmacological stimuli [5], [6].

Central mechanisms controlling water and salt intake and blood pressure are deeply interconnected. We have previously found that central 5-HT3 receptors are involved with these ingestive behaviors and that brain serotonin is an essential neurochemical component activated during stress [8], [12]. Taking these facts into account, in the present study we decided to investigate the role of brain 5-HT3 receptors in blood pressure regulation, both in non-stressed and stressed rats.

Section snippets

Animals

We used adult male Wistar rats (300±20 g), kept under controlled light (lights on from 5 a.m. to 7 p.m.) and temperature (24±2 °C) conditions. They had free access to tap water and laboratory chow (Nuvital Nutrientes, Curitiba, Brazil).

Surgical procedures

Six days before the experimental sessions, the third ventricles were cannulated under sodium pentobarbital anesthesia (50 mg/kg i.p.). In brief, after positioning the rat in a stereotaxic apparatus (David Kopf Instruments, USA), a chronic 28-gauge guide cannula

Results

Fig. 2 (panel A) depicts the effects of third ventricle injections of m-CPBG, a selective 5-HT3 agonist at different doses or saline solution (controls) on MAP in non-stressed rats. Analysis of variance for MAP indicated a significant treatment and time main effects and significant treatment x time interaction [F(3,24)=28.12, p<0.0001; F(10,30)=9.48, p<0.0001; F(30,240)=4.46, p<0.001, respectively]. Control animals did not exhibit any significant modification in MAP after third ventricle

Discussion

In the present paper, we decided to study the effects of pharmacological manipulations on central 5-HT3 receptors by injecting the drugs intracerebroventricularly instead of opting to study the role of 5-HT3 receptors located in any particular region of the brain. The reason for this choice is that the numerous pharmacological agents used in clinical therapeutics (as anti-emetics in cancer chemotherapy, for example) are systemically administered and reach the brain as a whole. The approach we

Acknowledgments

We are grateful to Mr. Vanilson Souza for his skilled technical assistance and to Mr. José de Souza for the animal care. The present work was supported through grants provided by the Brazilian Council of Research (CNPq), process no. 46.0104/00-4 and by the Financial Agency for the Support of Research in the State of Bahia (FAPESB).

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