Interaction between Dopaminergic and Angiotensinergic Systems on Thirst in Adult Male Rats

Z. Sharifkhodaei, N. Naghdi, S. Oryan

Department of Biology,Science faculty, Tarbiat Moallem University, Tehran, Iran.
Department of Physiology & Pharmacology, Pasteur Institute, Tehran, Iran.

DOI: 10.4236/nm.2012.31012                

Abstract

Thirst, which provides the motivation to drink, is an important component of the coordinated sequence of physiological responses that maintain the volume and composition of body fluids. Special structures in the central nervous system like periventricular organs detect changes in these parameters continuously. The present study investigated the interaction between dopaminergic and angiotensinergic systems on water intake in adult male rats. Intracerebroventricular (ICV) injections were carried out in all experiments after 24 h deprivation of water intake. After the deprivation interval, the volume of consumed water was measured for 1h. Administration the angiotensinergic (AT1) receptor antagonist Losartan (45 μg/rat), and the dopaminergic antagonist Chlorpromazine (40 μg/rat) significantly decreased water intake when compared to saline-treated controls. In contrast, ICV microinjection of the dopaminergic agonist Bromocriptine (10 μg/rat) significantly increased water intake when compared to saline-treated controls. ICV injection of Bromocriptine 15min after Losartan administration was able to attenuate the inhibitory effect of Losartan on water intake, whereas administration of Chlorpromazine 15 min after Losartan was unable to change the Losartan effect. These results suggest that the dopaminergic system interactions with the angiotensinergic system to regulate water intake through circumventricular organs. Dopaminergic and angiotensinergic neurons can monitor and regulate water intake via the stimulatory and inhibitory effects on each other, respectively.

Keywords

Water Intake; Drinking; Dopaminergic Receptors; Angiotensinergic Receptors; Thirst; Rats

1. Introduction

Thirst and salt appetite are important behaviors that help mammals to regulate plasma osmolarity, blood volume and blood pressure [1,2]. Thirst, which provides the motivation to drink, is an important component of the coordinated sequence of physiological responses that maintain the volume and composition of body fluids [3]. The homeostatic regulation of fluid intake by the brain is multifactorial: Osmotic, ionic, hormonal, and nervous signals converge on, and are integrated within, the central nervous system [3]. Specialized structures located both in the central nervous system and in strategic peripheral sites detect changes in these parameters continuously and accurately [2]. There is evidence that some osmoreceptors and osmoreceptive neurons are situated in the preoptic/hypothalamic region of the brain, rostral tissue in the anterior wall of the third ventricle (AV3V) [4], fourth and lateral ventricles [5], dorsal part of the organum vasculosum of the lamina terminalis (OVLT), the periphery of the sufornical organ (SFO) [3], median preoptic nucleus (MnPO) [4], lateral hypothalamic area and the hypothalamic paraventricular nucleus [3,6]. The MnPO receives afferent neural input from neurons in both the SFO and the OVLT and may integrate neural signals coming from osmoreceptive neurons in these circumventricular organs with visceral sensory inflow from the hindbrain [3]. Afferent input form the cardiopulmonary and arterial baroreceptors is carried to the brain by the IXth and Xth cranial nerves, with most of these nerves terminating in the nucleus of the solitary tract (NST) [7]. The nucleus tractus solitarius and the area postrema signal to lateral parabranchial nucleus that in turn signal to median preoptic nucleus. In addition, the area postrema and nucleus tractus solitarius also signal directly to subfornical organ [3]. Based on information obtained by these sensors, the central nervous system initiates responses including the stimulation or the inhibition of water and salt intake [1,2].

Previous studies have shown that a rapid and large intake volume of water and an increase in blood pressure occur immediately after the injection of angiotensin II into the cerebral ventricles or the preoptic region. This is a clear indication that central angiotensinergic system could cause thirst. Furthermore, centrally administered Ang II receptor antagonists are known to eliminate the drinking response [8].

Moreover, MnPO neurons are stimulated by angiotensinergic projection originating from the SFO and project towards vasopressinergic and oxytocinergic neurons of the PVN. When Ang II injected directly into these areas, an increase in water intake followed by an increase of sodium consumption subsequently occurs [9].

Also some studies indicate that dopaminergic neurons are highly concentrated in sev eral locations including substantia nigra (SN) [10], ventral tegmental area (VTA) [10], median eminence, hypothalamic [10,11], accumbens, caudate nuclei [12,13] and amygdala [12]. The data demonstrate that dopamine is required within the CNS for numerous roles including the control of water intake [11,13], food intake [11,12], locomotor activity [12], cognitive processes, learning task [12], and anxiety [12] adaptive situation. Other studies indicate that activation of dopaminergic neurons within the central thirst-related system is crucial for initiating physiological events underlying drinking behavior [14]. Dipsogenic signals generated by AII at the POA are transferred to the SFO through the catecholaminergic nerve fibers [15]. Extensive studies [12] demonstrate that the most effective site for producing adipsia is an intermediate zone between the substantia nigra and VTA. Additionally, the nigrostriatal, caudate and accumbens nuclei [13] and the lateral hypothalamus [11] are involved in regulation of water intake.

Previous research has shown that intracranial injections of DA antagonist significantly reduce water intake and block angiotensin-induced drinking [16]. D₁ receptor antagonists (SCH 23390) substantially reduce water intake and have greater role in control of water intake. Antidopaminergic agents (haloperidol) with pronounced antidopaminergic actions on D₂ receptors reduce the water intake of rats [13]. DA agonist administration in the lateral hypothalamus reduce water intake and DA antagonist promote drinking [17].

In the present study, we investigate the interaction between the dopaminergic and angiotensinergic systems on water intake in adult male rats specifically regarding the role of the central angiotensinergic and dopaminergic systems on water deprivation induced thirst.

2. Materials and Methods

2.1. Animals

Adult male Wistar rats (200 - 250 g) were obtained from the breeding colony of Tarbiat Moallem University of Tehran. Rats were housed three per cage, but one day before test day one per cage, in a temperature (23˚C ± 1˚C) controlled room that was maintained on a 12 hour on: 12 hour off light cycle (light on at 07:00 am). Rats had unrestricted access to food and water in their home cage. The type of food was pellet and it was purchased from Khorak Dam Pars Co. in Iran.

These animal experiments were carried out in accordance with recommendations from the declaration of Helsinki and the internationally accepted principles for the use of experimental animals.

2.2. Surgical Procedures

The rats were anesthetized with ketamine-xylazine (100 mg/kg ketamine 5 mg/kg xylazine). The skull was leveled between bregma and lambda. A stainless steel 21- gauge guide cannula (0.8 mm) was implanted above the lateral cerebral ventricle using coordinates from the atlas of Paxinos and Watson at least 5 - 7 days before testing. The coordinates used were 0.8 mm posterior to the bregma, 1.3 mm lateral to the midline and 3.4 mm below the top of the skull. The cannula was fixed to the skull using one screw and dental acrylic.

2.3. Microinjection Procedure

Intracerebroventricular (ICV) injections were made via guide cannulae with injection needles (27-gauge) that were connected by polyethylene tubing to a 10 µl Hamilton microsyringe. The injections (0.5 µl total volume) were delivered over two minutes with a syringe pump, and the injection needles (extending 1.5 mm from the end of the guide cannulae) were left in place an additional minute before they were slowly withdrawn.

2.4. Drugs

The drugs included Bromocriptine methanesulfonate (Hakim Pharmaceutical company, Iran), a dopaminergic D₂ receptor agonist, Chlorpromazine hydrochloride (Sigma), a dopaminergic D₂ receptor antagonist, and Losartan potassium (Sigma), an angiotensinergic AT₁ receptor antagonist. All the drugs were dissolved in saline. The drugs were used (ICV) in a volume of 0.5 µl/rat.

2.5. Experimental Procedures

The experiments were performed in conscious freely moving rats 5 - 7 days post surgery. Forty-eight adult male rats were divided into 18 groups of 6 rats per group. Group 1 received sham operations. Groups 2, 3, and 4 received Bromocriptine (5, 10, or 20 µg/rat). Groups 6, 7, and 8 received Chlorpromazine (20, 40, or 80 µg/rat). Groups 9, 10, and 11 received Losartan (22.5, 45, or 90 µg/rat). Group 13 received sham operations and two ICV injections of saline 15 min apart. Group 14 received Losartan (45 µg/rat) 15 min after ICV injection of saline. Group 15 received Bromocriptine (10 µg/rat) 15 min after ICV injection of saline. Group 16 received Bromocriptine (10 µg/rat) 15 min after ICV injection of Losartan (45 µg/rat). Group 17 received Chlorpromazine (40 µg/rat) 15 min after ICV injection of saline. Group 18 received Chlorpromazine (40 µg/rat) 15 min after ICV injection of Losartan (45 µg/rat).

All rats were deprived of water for 24 h prior to each test day. Food was available during deprivation period but not during the test period. The food pellets may have had an interaction with thirst; however this condition was similar for all animals and consequently had no effect on our results. After 24 h water deprivation, saline or drugs were injected (ICV) over a period of 90 s, and water in graduated glass cylinders was returned to each cage. Groups received two injections: a control saline injection followed 15 min later by injection of a drug, or one drug followed 15 min later by another drug to determine the effect of the first drug on the response to the second. In the control groups with two injections, saline was injected 15 min before a second administration of saline. Immediately after the last injection, water intake was recorded for 1 h by reading from the graduated glass cylinder mounted on the wall of the cages. All experiments were conducted between 9 am and 11 am and each rat was tested only once.

The proposal was established and approved by the Research and Animal Ethical Committees of Tarbiat Moallem University,Tehran, Iran.

2.6. Data Analysis

Data are reported as one way ANOVA followed by Tukey or Dunnett to test statistical significance. Differences were considered significant at p < 0.05.

2.7. Histology

Following behavioral testing, animals were sacrificed by decapitation and the brains were removed and fixed in formalin. For histological examination of cannulae and injection placement in the lateral ventricle, 100 μm thick sections were taken and cannulae and injection tracks were examined with light microscopy. Only data obtained from animals whose cannulae and injections were exactly placed in the lateral ventricle were included for analysis.

3. Results

Experiment 1: The effect of ICV injection of D₂ receptor agonist and antagonist at different doses on water intake in fluid-deprived rats.

Figure 1 shows the effect of ICV injection of Bromocriptine and Chlorpromazine at different doses on water intake in fluid-deprived rats. One way ANOVA analysis indicated that there was a significant increase in water intake at a dose of 10 µg/rat Bromocriptine (p < 0.01) in comparison to saline-treated controls. F (3, 20) = 6.427, (n = 6). And there was a significant decrease in water intake at a dose of 40 µg/rat Chlorpromazine (p < 0.05) in comparison to

Conflicts of Interest

The authors declare no conflicts of interest.

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