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Institut National de la Santé et de la Recherche Médicale U288, Faculté de Médecine Pitié-Salpêtrière, 75634 Paris Cedex 13, France
Submitted 16 December 2003 ; accepted in final form 18 May 2004
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ABSTRACT |
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 TOP ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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nucleus tractus solitarius; serotonin3 receptors; GABAA receptors; defense/attack
Inhibition of the baroreceptor reflex bradycardia caused by NTS 5-HT3 receptor stimulation seems to be mediated through the activation of a local GABAergic system because it could be abolished by prior intra-NTS application of bicuculline, a GABAA receptor antagonist (15). Interestingly, the latter treatment was also found to prevent the inhibition of NTS barosensitive neurons that normally occurs during the defense reaction (10).
All of these data led us to postulate that both 5-HT3 and GABAA receptors in the NTS are implicated in the defense reaction-induced inhibition of the cardiac baroreflex response. In line with this idea, we recently showed that the baroreflex inhibition normally observed during electrical stimulation of structures that elicit the defense reaction, including the dorsal part of the periaqueductal gray (dPAG; Refs. 2 and 3), could be prevented by intra-NTS microinjections of granisetron, a specific 5-HT3 receptor antagonist (8), as well as bicuculline (26).
However, to really establish that serotonergic receptors actually mediate the defense reaction-induced inhibition of the baroreflex, it is also necessary to demonstrate that their stimulation by endogenous 5-HT is a key component of underlying inhibitory mechanisms. To this goal, we analyzed the effects of dPAG stimulation on the bradycardiac baroreflex response in rats that had been pretreated with p-chlorophenylalanine (PCPA), a serotonin synthesis inhibitor (12). For these experiments, the baroreceptor reflex was triggered by either systemic injection of phenylephrine or electrical stimulation of the aortic depressor nerve. In addition, we investigated whether 5-HT3 and/or GABAA receptors in the NTS mediated the inhibitory effect of electrical and chemical dPAG stimulation on the baroreflex cardiac response to phenylephrine administration. For this purpose, both receptors were specifically blocked by intra-NTS microinjections of selective antagonists.
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MATERIALS AND METHODS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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Experiments were performed on 116 male Sprague-Dawley rats weighing 330–370 g. Animals were kept under controlled environmental conditions (ambient temperature: 21 ± 1°C, 60% relative humidity, food, and water ad libitum, alternate 12:12-h light-dark cycles) for at least 1 wk after receipt from the breeding center (CER Janvier; Le Genest-St. Isle, France). Procedures involving animals and their care were all conducted in conformity with the institutional guidelines, which are in compliance with national and international laws and policies [Council Directive no. 87-848, 19 October 1987, Ministère de l'Agriculture et de la Forêt, Service Vétérinaire de la Santé et de la Protection Animale, permissions no. 75-116 (to M. Hamon) and no. 75-117 (to R. Laguzzi)].
Rats were anesthetized with urethane (1.5 g/kg ip), and the depth of anesthesia was regularly assessed by pinching a hindpaw and monitoring the stability of BP and HR. In case of withdrawal reflex and/or variations of cardiovascular parameters, a supplementary dose of urethane was given (0.1–0.2 g/kg iv). A cannula was inserted into the femoral vein for administration of drugs and/or additional doses of urethane. Systemic BP, mean BP (MBP), and HR were monitored (Pressure Processor and DC Amplifier, Gould; Courtaboeuf, France) through a catheter inserted into the femoral artery. ECG was recorded with the use of stainless steel pins placed subcutaneously into fore- and hindpaws; signals were amplified and filtered (Universal Amplifier, Gould). The R wave of ECG was discriminated with a window discriminator and used to generate pulses. Arterial BP and ECG pulse signals were relayed to a 1401 interface (1401 Plus, CED) connected to a computer running Spike 2 software (CED; Cambridge, UK). HR was automatically computed from R wave pulses and displayed as mean frequency per minute (bin size: 1 s). Rectal temperature was maintained at 37°C with a thermostatically controlled heating blanket.
Procedures for dPAG Stimulation and Intra-NTS Microinjections
The rats were placed in a stereotaxic frame with the head fixed in horizontal position. A craniotomy was performed, and either a bipolar stimulating electrode or a single-barrel glass micropipette (<100 µm external diameter), connected to a Hamilton microsyringe (filled with bicuculline in saline), was lowered into the dPAG using stereotaxic coordinates (P 6.7, L 0.7, V 3.5–4.5) from Paxinos and Watson's atlas (20). In both cases, dPAG was identified by observing body reactions and cardiorespiratory responses typical of the defense reaction caused by local electrical stimulation (50 Hz, 1 ms pulse duration, 200 µA, Ref. 26) or bicuculline microinjection (100 pmol in 100 nl): mydriasis, vibrissae and body movements, tail erection, rise in BP, tachycardia, and hyperventilation. In addition, stimulation of the dPAG by bicuculline (but not by electrical pulses) produced a slight and nonsignificant delayed increase in the variability of MBP that occurred 2–5 s after BP had reached its maximal value. In some rats, the left aortic depressor nerve was dissected out from the vagus nerve by a lateral approach and placed on silver bipolar hook electrodes for electrical stimulation.
For microinjections of neuroactive substances into the NTS, the dorsal surface of the brain stem was exposed through a limited occipital craniotomy. A single-barrel glass micropipette (<100 µm external diameter), connected to a Hamilton microsyringe filled with drugs or saline, was lowered into the commissural NTS, 0.5 mm lateral to the calamus scriptorius and 0.5 mm beneath the dorsal surface of the medulla (26). Microinjections (100 nl) were made over 2 s with a pneumatic microinfusion pump and the micropipette was removed 15 s after the injection. The same micropipette was used for bilateral microinjections of a given drug. The time interval between two symmetrical microinjections was <1 min.
Atenolol Administration
Because our purpose was to analyze the effects of dPAG stimulation on reflex vagal bradycardia, all rats used in the present study were pretreated with atenolol (1 mg/kg iv; 20 min before phenylephrine injection or aortic nerve stimulation), a 
-adrenergic receptor antagonist to eliminate both the influence of the defense reaction-induced sympathetic activation on HR and the sympathetic cardioinhibitory component of the baroreflex (29). Systemic administration of atenolol produced a rapid and significant decrease in HR (
HR: –42 ± 5 beats/min from a baseline of 348 ± 4 beats/min, paired Student's t-test, P < 0.05, n = 116) without affecting BP (MBP = –2 ± 1 mmHg from a baseline of 81 ± 1 mmHg, n = 116). HR and MBP baseline values then remained stable for at least 2 h. In addition, this treatment blocked for >1 h the increase in HR normally evoked by dPAG stimulation and induced a slight but nonsignificant reduction (–5%) of baroreflex bradycardia.
Baroreflex Activation
The baroreflex was triggered either by a bolus injection of phenylephrine at a dose (10 µg/kg iv) sufficient to elevate MBP by 50–60 mmHg, or by electrical pulses (20 Hz, 1 ms pulse duration) applied to left aortic depressor nerve. The intensity of aortic nerve stimulation was adjusted (100–150 µA) to elicit the maximal aortic cardiac-evoked response (HR: –170 to –190 beats/min) that could be obtained without producing nerve damage, according to the criteria fixed by Sévoz-Couche et al. (26).
Quantification of Cardiac Baroreflex Response
In phenylephrine-injected rats, the cardiac reflex response (PECR) was assessed from the ratio of the maximal increase in HR (HRmax) over the maximal increase in MBP (MBPmax) caused by the drug. In addition, we drew the curve of phenylephrine-induced baroreflex gain and calculated the cardiac baroreceptor sensitivity from its rectilinear part by fitting the data with a common sigmoid curve equation (4)
 | (1) |
In rats whose aortic depressor nerve was stimulated, the evoked cardiac response (ACR) was expressed as the ratio of HRmax caused by the stimulation over its corresponding baseline value (HR baseline).
Inhibition of Cardiac Baroreflex Responses by dPAG Stimulation
To assess the effects of dPAG stimulation on cardiac reflex responses normally evoked by phenylephrine administration, PECR were first determined after injection of the 
1-adrenoreceptor agonist alone ("PECR control"). Then, 10 min later, "PECR experimental" was determined in response to a second injection of phenylephrine made simultaneously with electrical stimulation of dPAG or when the increase in MBP induced by intra dPAG microinjection of bicuculline (chemical stimulation) reached its maximum value. Electrical dPAG stimulation could be performed several times in each rat. In these conditions, three successive determinations of PECR control-PECR experimental could be made (within 30 min). Corresponding values were considered as stable when they differed by <10%. Only the last one was taken into account for statistical analysis.
In contrast, only one chemical stimulation of dPAG could be made in a given rat. Therefore, only one determination of PECR control-PECR experimental was performed in rats microinjected with bicuculline within dPAG.
To quantify the inhibition of the aortic cardiac response caused by dPAG stimulation, ACR was first evoked by aortic nerve stimulation during 4 s ("ACR control"). Five minutes later, when MBP and HR had returned to baseline levels, electrical stimulation of dPAG was turned on and the aortic nerve was stimulated again ("ACR experimental") for 4 s when the cardiovascular changes associated with the evoked defense reaction were maximal (i.e., 
3 s after the beginning of dPAG stimulation). Stimulation of dPAG was then turned off 3 s after the end of aortic nerve stimulation. Three successive determinations of "ACR control-ACR experimental" were performed (within 10 min). Corresponding values were considered stable when they differed by <10%. Only the last one was used for statistical analysis.
Pharmacological Treatments
Systemic treatments with PCPA and 5-HTP. Two groups of rats were treated daily (at 8 PM), during 3 consecutive days, with PCPA at the dose of 300 mg/kg ip. In these animals, either PECR (n = 15) or ACR (n = 15) was determined 12 h after the last PCPA injection. Such determinations were carried out under basal conditions and during electrical stimulation of dPAG (as described above). Paired controls received saline instead of PCPA and were used for PECR (n = 6) or ACR (n = 6) determinations also under baseline and dPAG stimulating conditions. In addition, in a fraction of PCPA-treated rats, the effects of dPAG stimulation on PECR (n = 6 out of 15) and ACR (n = 6 out of 15) were also tested before and after (60 min) administration of the 5-HT precursor 5-HTP (60 mg/kg ip).
Intra-NTS administrations of granisetron and bicuculline. These treatments were performed in combination wih either electrical or chemical stimulation of dPAG. Electrical stimulation (n = 36) was performed in three different groups of rats (groups A, B, and C) for the determinations of PECR control (before stimulation) and experimental (during stimulation) before and after (15 and 60 min) bilateral intra-NTS micronjections of the following: group A, saline (n = 6); group B, granisetron (250 pmol, n = 15), or group C, bicuculline (5 pmol, n = 15) (see Table 1).
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Histology. At the end of the experiments, electrolytic lesions (50 Hz, 4 mA, 20 s) were made at dPAG stimulation sites, and methylene blue (0.1 µl) was microinjected into the injection sites within NTS and dPAG. Rats were then perfused intracardially with saline and a solution of 4% paraformaldehyde in 0.1 M sodium phosphate, pH 7.4. After perfusion, the brain was removed from the skull, and coronal sections (60 µm) were cut and stained with neutral red.
Statistical Calculations
Absolute values are expressed as means ± SE of n rats. Statistical analyses were performed using paired and unpaired Student's t-test or two-way ANOVA as appropriate (see RESULTS). A difference was considered significant at P < 0.05.
Drugs
Atenolol (Sigma-Aldrich; St. Quentin-Fallavier, France), bicuculline methiodide (Sigma-Aldrich), DL-p-chlorophenylalanine methyl ester (Sigma-Aldrich), granisetron (Glaxo Smith Kline; Harlow, UK), 5-hydroxy-L-tryptophan (Sigma-Aldrich), phenylephrine (Chibret; Paris, France), and urethane ethyl-carbamate (Sigma-Aldrich) were dissolved in saline. The pH of all solutions microinjected into the dPAG or the NTS was adjusted to 7.4.
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RESULTS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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In naive rats, administration of phenylephrine (10 µg/kg iv, n = 62) induced an increase in BP of +53 ± 1 mmHg from a baseline of 79 ± 3 mmHg, which triggered a cardiac reflex response of –117 ± 5 beats/min from a baseline HR of 304 ± 4 beats/min (paired Student's t-test, P < 0.05). Electrical stimulation of dPAG (Fig. 1A) performed before any intra-NTS microinjections increased BP (MBP = 101 ± 3 vs. 80 ± 2 mmHg, +26%; paired Student's t-test, n = 36, P < 0.05) and markedly reduced the cardiac response normally induced by phenylephrine (PECR control and experimental: 2.07 ± 0.03 and 0.55 ± 0.02 beats·min–1·mmHg–1, respectively, –73%, paired Student's t-test, n = 36, P < 0.05) (Fig. 2A). Consequently, dPAG electrical stimulation produced a flattening of the baroreflex gain curve (Fig. 3). In the same manner, dPAG chemical stimulation by local microinjection of bicuculline (Fig. 1B) induced an increase in BP (110 ± 3 vs. 80 ± 4 mmHg, +37.5%, paired Student's t-test; n = 26, P < 0.05) and significantly reduced phenylephrine-evoked cardiac response (PECR control and experimental: 2.01 ± 0.03 and 0.80 ± 0.01, respectively, –60%, n = 7, paired Student's t-test, P < 0.05) (Fig. 2B).
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Effects of dPAG Stimulation on Baroreflex Cardiac Responses in PCPA-Treated Rats
Biochemical controls showed that PCPA treatment almost totally depleted 5-HT (36 ± 2 vs. 539 ± 39 ng/g in paired saline-treated controls, –93%, n = 6 in each group, unpaired Student's t-test; P < 0.05) and 5-hydroxyindoleacetic acid (15 ± 1 vs. 338 ± 32 ng/g in PCPA and saline-treated rats, respectively, –96%, n = 6 in each group, P < 0.05) levels in the brain stem. In these animals, as well as in paired saline-treated controls, the increase in BP normally produced by dPAG electrical stimulation (PCPA: +20 ± 3 mmHg from a baseline of 81 ± 4 mmHg, n = 30; saline: +25 ± 5 mmHg from a baseline of 78 ± 4 mmHg, n = 12), and both PECR (PCPA: 2.09 ± 0.03, n = 15; saline: 2.05 ± 0.03 beats·min–1·mmHg–1, n = 6) and ACR (PCPA: 0.39 ± 0.02 beats·min–1·mmHg–1, n = 15; saline: 0.41 ± 0.03 beats·min–1·mmHg–1, n = 6) did not significantly differ from those observed in naive untreated rats (see above). In contrast, treatment with PCPA but not saline (n = 6 for each evoked cardiac response) prevented the reduction of PECR (Fig. 4A, n = 15) and ACR (Fig. 4B, n = 15) normally produced by dPAG electrical stimulation.
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Effects of Intra-NTS Microinjections of Granisetron on Inhibition of Phenylephrine-Induced Bradycardia by dPAG Stimulation
Bilateral microinjections of granisetron (250 pmol) into the commissural NTS (Fig. 1C) did not significantly modify cardiovascular parameters (MBP = +2.1 ± 1.0 mmHg from a baseline of +81 ± 2 mmHg; HR = +11 ± 5 beats/min from a baseline of 296 ± 6 beats/min, n = 28) and PECR (Table 1). However, such microinjections, but not those of saline in paired control rats (n = 6, Tables 1 and 2, Fig. 5A), markedly reduced (by about –80%) for 45 min the inhibitory effects of both electrical (n = 15, Table 1) and chemical (n = 7, Fig. 5B, Table 2) stimulation of dPAG on PECR. Consequently, the flattening effect of dPAG stimulation on the baroreflex gain curve was no longer observed in rats that had been microinjected with granisetron (Fig. 3A). As expected, the effect of intra-NTS microinjection of granisetron and that of systemic administration of PCPA were not additive (PECR control and experimental were 2.00 ± 0.02 and 1.79 ± 0.03, respectively, in PCPA-treated rats before granisetron, and 2.02 ± 0.03 and 1.81 ± 0.04, respectively, in PCPA-treated rats after granisetron, n = 6).
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Bilateral microinjections of a low dose of bicuculline (5 pmol) into the commissural NTS (Fig. 1C) produced no significant changes in HR (HR = –2.0 ± 1.9 beats/min, from a baseline of 295 ± 5 beats/min, n = 21) and MBP (MBP = +2.0 ± 1.8 mmHg, from a baseline of 79 ± 3 mmHg, n = 21), and did not affect PECR (Table 2). However, the decrease in PECR as well as the flattening of the baroreflex gain curve normally caused by dPAG electrical stimulation were prevented by intra-NTS administration of bicuculline (n = 15, Table 1 and Fig. 3B). Similarly, the latter treatment (n = 6) markedly attenuated PECR inhibition normally caused by dPAG chemical stimulation (Table 2 and Fig. 5C). Such effects of intra-NTS bicuculline microinjections lasted 35 min.
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DISCUSSION |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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In our previous studies (26) demonstrating that dPAG stimulation was able to inhibit baroreflex bradycardia, the baroreflex was triggered by direct electrical stimulation of the aortic depressor nerve and its inhibition was evaluated by comparing the magnitude of the maximal reflex responses before (ACR control) versus during (ACR experimental) the latter stimulation. The use of phenylephrine to trigger the baroreflex in the present study permitted us not only to compare the magnitude of the maximal reflex responses (PECR experimental vs. PECR control) but also, as explained in MATERIALS AND METHODS, to determine the slope of the baroreceptor gain curve under control versus experimental conditions. Thus comparison of respective slopes allowed quantitative estimates of the inhibitory effects of dPAG stimulation on sensitivity of the cardiac baroreflex response. The data reported herein clearly demonstrated that electrical stimulation of the dPAG triggered a marked reduction in both PECR and the sensitivity of the cardiac baroreceptor reflex response.
Because phenylephrine produces a general vasoconstriction, the evoked cardiac reflex response in fact results from both aortic and carotid sinus baroreceptor stimulation. Thus if dPAG stimulation had no effect on the cardiac response to carotid sinus receptor stimulation, the resulting attenuation of PECR would have been less than that of ACR. Indeed, our data showed that the magnitude of the inhibition of PECR and ACR by dPAG stimulation was actually similar, thereby indicating that the latter stimulation affected not only aortic but also carotid baroreceptor cardiac responses.
Previous studies (17) have suggested that dPAG stimulation could exert an inhibitory influence on the cardiac component of the baroreceptor reflex through the local activation of not only cell bodies but also fibers "en passage." However, chemical stimulation by bicuculline excites cell bodies only, and our observations that electrical and chemical stimulation of the dPAG produced similar inhibition of PECR strongly support the idea that cell bodies in the dPAG but not fibers en passage are implicated in the inhibition of the baroreflex during the defense reaction.
Data reported herein showed that 5-HT synthesis inhibition by PCPA almost totally prevented the inhibitory effects of dPAG stimulation on the cardiac response elicited by either phenylephrine administration or aortic nerve stimulation. Moreover, 5-HT implication in the inhibitory influence of dPAG stimulation is confirmed by the fact that 5-HTP administration, to restore 5-HT synthesis in PCPA-pretreated rats, allowed recovery of this negative control of both aortic and phenylephrine-induced cardiac reflex responses as the same level as that observed in naive rats. However, PCPA treatment did not affect the increase in BP induced by dPAG electrical stimulation, further confirming that 5-HT is not involved in this defense reaction-induced response (26).
Anatomic data support the idea that the NTS might be one of the structures where serotoninergic neurotransmission is implicated in at least some of the autonomic changes associated with behavioral reactions to stressful conditions. Thus numerous projections from the dPAG and the hypothalamus to different raphe nuclei have been described (7, 22, 31), and the latter nuclei are well known to be a major source of serotoninergic fibers terminating within the NTS (24, 28, 30). Our previous studies (26) suggested the participation of NTS 5-HT3 receptors in the electrical dPAG stimulation-induced inhibition of the cardiac component of the aortic baroreceptor reflex. The data reported herein actually confirmed and extended them. Indeed, we showed here that intra-NTS administration of granisetron, a selective 5-HT3 receptor antagonist (8), prevented the inhibition of PECR normally observed during either electrical or chemical stimulation of the dPAG. Accordingly, it can be inferred that NTS 5-HT3 receptors are critically involved in the dPAG-mediated inhibition of the reflex bradycardia normally evoked by general baroreceptor activation at the periphery. Furthermore, the fact that 1) granisetron and PCPA prevented to the same extent the inhibitory effect of dPAG stimulation on the baroreflex bradycardia, and 2) there was no additional effect of granisetron in PCPA-pretreated rats strongly support the idea that the action of endogenous 5-HT in such an inhibitory control is mediated through the stimulation of NTS 5-HT3 receptors.
The data reported herein also confirmed and extended those of our previous studies (15, 26), which suggested that inhibition of the baroreceptor reflex bradycardia by NTS 5-HT3receptor stimulation involves a local GABAergic system. Indeed, we found that the inhibitory effect of dPAG electrical or chemical stimulation on PECR could be blocked not only by intra-NTS microinjections of a 5-HT3 receptor antagonist, granisetron, but also by local microinjections of a GABAA receptor antagonist, bicuculline. Taking into account these and previous data, it can be hypothetized that the inhibition by dPAG stimulation of the cardiovagal component of the baroreceptor reflex implies the following sequence: 1) excitation (by electrical or chemical stimulation) of dPAG cell bodies triggers the release of endogenous 5-HT within the NTS and consequently the activation of local presynaptic 5-HT3 receptors (21, 23); 2) stimulation of these receptors on vagal afferent fibers promotes the local release of glutamate (1), which, in turn, activates GABAergic interneurons; and 3) the resulting stimulation of GABAA receptors finally exerts an inhibitory influence on NTS neurons at the origin of the aortic and carotid cardiac responses of the baroreceptor reflex.
Histological controls performed in the present and previous (26) studies revealed that methylene blue microinjected into the NTS did not reach the area postrema but spread to the dorsal vagal nucleus (data not shown). Although the latter nucleus contains 5-HT3 and GABAA receptors as well as preganglionic vagal motoneurons, its contribution to the defense reaction-induced inhibition of the baroreflex bradycardia is unlikely because the vagal motoneurons, which participate in the reflex control of HR, are almost exclusively located in the nucleus ambiguus in rats (14, 27).
In conclusion, the data reported herein show that serotoninergic neurotransmission plays a key role in the reduction of the aortic and carotid baroreceptor cardiac reflex response produced by electrical and chemical dPAG stimulation in the rat. Moreover, these data confirm and complete previous results (26), which already suggested that the inhibitory influence of endogenous 5-HT triggered by dPAG stimulation is actually mediated through the stimulation of 5-HT3 receptors in the NTS, and that local GABAA receptors contribute downstream to this effect.
Altogether, these data contribute to the elucidation of mechanisms underlying inhibition of the cardiac component of the baroreceptor reflex during stressful conditions. Such mechanisms are especially important because the resulting cardiovascular adaptations allow performance of appropriate behavioural reactions in stressed animals (17). Physiopathological relevance can also be emphasized because the defense reaction in the rat is known to share the same central pathways as panic disorders in humans (5).
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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