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• W1501888346 abstract "Anxiety disorders reduce both the heart rate variability (HRV) and the sensitivity of the cardiac baroreflex (BRS). This may lead to sudden cardiac death. To elucidate the mechanisms underlying these alterations, male rats were subjected to social defeat sessions that lead to an anxiety-like state. In this model, HRV and BRS were reduced, reflex of a shift of the autonomic balance towards sympathetic predominance. Pharmacological blockade of the dorsomedial hypothalamus (DMH) reversed all cardiovascular alterations, whereas blockade of the nucleus tractus solitarii (NTS) 5-HT3 receptor by the local or systemic administration of granisetron restored only baroreflex gains and the parasympathetic component of HRV. In conclusion, repeated social defeat in the rat leads to an anxiety-like state, in which the DMH and the NTS are chronically activated and are responsible for dysautonomia. These regions may constitute new targets against sudden cardiac death. Abstract Anxiety disorders in humans reduce both the heart rate variability (HRV) and the sensitivity of the cardiac baroreflex (BRS). Both may contribute to sudden death. To elucidate the mechanisms underlying these alterations, male rats were subjected to social defeat sessions on four consecutive days. Five days later, the rats were found to be in an anxiety-like state. At this time point, we analysed HRV and BRS in the defeated rats, with or without treatment with the anxiolytic chlordiazepoxide (CDZ). HRV was reduced after social defeat, due to changes in the autonomic balance favouring the sympathetic over the parasympathetic component. Spontaneous and pharmacological baroreflex gains were also reduced. CDZ abolished anxiety-like symptoms as well as HRV and BRS alterations. Inhibition of the dorsomedial hypothalamus (DMH) with muscimol reversed all cardiovascular alterations, whereas blockade of the nucleus tractus solitarii (NTS) 5-HT3 receptor by the local or systemic administration of granisetron restored only baroreflex gains and the parasympathetic component of HRV. In conclusion, repeated social defeat in the rat lead to an anxiety-like state that was associated with lasting reduction in HRV and baroreflex gains. The DMH and the NTS were responsible for these chronic cardiovascular alterations. These regions may therefore constitute new therapeutic targets for reducing cardiac dysfunction and fibrillation in anxiety disorders. Mood disorders are associated with the occurrence of ventricular arrhythmia (Francis et al. 2009; Brugada, 2012). There is a solid body of evidence linking the autonomic nervous system to life-threatening arrhythmia and death from cardiovascular causes (Watkins et al. 1998; Friedman, 2007), as reduction of heart rate variability (HRV) and the baroreceptor-heart rate (HR) reflex (baroreflex sensitivity, BRS) have been shown to be predictive of the occurrence of ventricular fibrillation (Billman et al. 1982; Schwartz, 1998; La Rovere et al. 2001). However, the mechanisms underlying these cardiac alterations are still unknown. A limited number of studies have been conducted in animal models of these diseases, to analyse cardiac and autonomic dysfunctions. Some of these studies used experimentally (Moffitt et al. 2002) or genetically (Padley et al. 2005) modified animals, while others used systems more closely resembling the physiological reactions observed in humans following the application of a chronic stress (Sgoifo et al. 2002; Grippo et al. 2008). However, only a few of these studies have analysed the cardiac BRS. Analyses of BRS during or at the end of a chronic stress inducing depression suggested that this parameter was not affected (Grippo et al. 2008; Porter et al. 2004). Thus, our principal objective was to analyse the long-term effects on HRV and the BRS during an anxiety-like state induced by repeated social defeat (Rivat et al. 2010), one of the most severe known stressors (Koolhaas et al. 1997). In an experimental design based on anticipation, intruder rats were repeatedly subjected to the threat of an aggressive conspecific resident, which was then allowed to attack and defeat them. This procedure has been shown to induce anxiety-like behaviour 5 days after the last session (Andréet al. 2005; Rivat et al. 2010; Blugeot et al. 2011). Thus, the aim of this study was to analyse the changes in autonomic balance and baroreflex gain associated with the establishment of this chronic stress-induced anxiety. We also explored the mechanisms that link anxiety to cardiovascular dysregulation. The dorsomedial hypothalamus (DMH) has been shown to activate sympathetic premotor neurons in the rostral ventro-lateral medulla (Wang et al. 2010), and to induce inhibition of the cardiac baroreflex response (BRR). This inhibition is mediated by the release of serotonin from the raphe magnus region, which acts onto presynaptic 5-HT3 receptors in the nucleus tractus solitarii (NTS; Merahi et al. 1992; Sévoz-Couche et al. 2003; Netzer et al. 2011). Knowing that DMH activation results also in anxiogenic-like effects (Shekhar, 1993; DiMicco et al. 2002), we hypothesized that the DMH, and consequently serotonergic receptors in the NTS, are chronically activated after social challenge sessions, and that this will alter cardiovascular parameters. We tested this hypothesis by pharmacological blockade of both regions in anaesthetized animals that had or had not been subjected to social defeat, 6 days after the last session. Male Sprague–Dawley rats (Centre d’Elevage R. Janvier, Le Genest-St.Isle, France) weighing 250–300 g were used as experimental intruder animals (n= 157). They were housed in individual cages from 7 days before the beginning of the social defeat procedure until the end of the protocol (D−7 to D10; Fig 1A). Wild-type Groningen male rats (Rattus norvegicus, WTG strain), originally reared at the University of Groningen (The Netherlands) under conventionally clean conditions and weighing 400–500 g were used as the resident rats in confrontation encounters. All animals were kept under controlled environmental conditions (22 ± 1°C; 60% relative humidity; 12 h light/dark cycle; food and water ad libitum). Procedures involving animals and their care were all performed in conformity with the institutional guidelines, which are in compliance with national and international laws and policies (Council directive 87–848, 19 October 1987, Ministere de l’Agriculture et de la Foret, Service Veterinaire de la Sante et de la Protection Animale; permissions 75855 to C. Sévoz-Couche and 6180 to J.-J. Benoliel). Long-term consequences of the social defeat protocol for physiological and behavioural parameters in non-defeated (ND) and defeated (D) rats with no treatment A, the experimental procedure consisted of four daily conditioning sessions (D1–D4) with the same pairs of residents and intruders. The elevated plus-maze test (EPM) was performed 5 days (D9) after the end of the social defeat procedure, and cardiovascular (CV) parameters and adrenal gland (AG) weight were measured on the following day (D10). Body weight was measured daily in ND and D rats, before, during and 6 days after conditioning sessions (D−7 to D10). B, D animals (n= 10) were lighter than ND (n= 10) animals. Differences were first observed the day after the first conditioning session (D2) and were maintained until the end of the protocol (D10). Each point is the mean ± SEM for D or ND rats. **P < 0.005 and ***P < 0.001 vs. ND rats. C, D animals had an increased AG weight and spent less time in the open arms of the EPM. Box–Whisker graphs with minimum and maximum values, lines are the medians. ***P < 0.001 vs. ND rats. Social defeat experimental procedure Social defeat (Rivat et al. 2010) involved four daily conditioning sessions (Fig. 1A) with the same pairs of residents and intruders (Becker et al. 2001). Briefly, intruders (defeated (D) animals) were placed singly in a protective cage inside the resident home cage, allowing unrestricted visual, auditory and olfactory contact with the resident but precluding close physical contact. The protective cage was then removed with the resident present, allowing physical confrontation with the intruder (D intruders). There were three–four confrontations of 10 s each, during which the intruding animal was always dominated by the resident rat. For non-defeated (ND) intruders, the intruder had access to the entire resident home cage in the absence of the resident. This social defeat procedure has been shown to induce an anxiety-like state 5 days after the last conditioning session (Rivat et al. 2010). Here, we checked that all D animals presented basic signs of anxiety not observed in ND rats. Body weight The body weights of D and ND rats were measured daily at 09.00 h, before (7 days, D−7 to D1), during (4 days, D1–D4) and after (6 days, D5–D10) the social defeat procedure. Elevated plus-maze test Five days after the end of the fourth conditioning sessions (D9; Fig. 1A), the elevated plus-maze test was used to evaluate anxiety-related behaviour in animals. This test has been described in detail elsewhere (Rivat et al. 2010). The time spent in the various arms, and the numbers of entries into the open and closed arms of the plus-maze were recorded with custom-made software. The total number (open + closed) of arm entries was taken as an indicator of general activity. Adrenal gland weight At the end of all experiments (D10; Fig. 1A), adrenal glands were removed, dissected free of adhering fat and weighed. Organ weights are expressed relative to total body weight (in mg (100 g body weight)−1). General procedures for the measurement of cardiovascular parameters On the morning after elevated plus-maze tests (D10; Fig. 1A), animals were anaesthetized with pentobarbital sodium (Ceva Santé Animale, Libourne, France; 60 mg kg−1, i.p.; Sévoz-Couche et al. 1998). The depth of anaesthesia was assessed regularly by pinching a hind paw and monitoring the stability of the arterial blood pressure (BP) and HR recordings. In case of withdrawal reflex and/or significant variations of these parameters, a supplementary dose of pentobarbital was given (10 mg kg−1, i.v.). Systemic BP and mean BP (MBP) were monitored via a femoral artery catheter. HR was calculated from the ECG (R-wave pulses) and displayed as mean frequency per minute (bin size = 1 s), and the mean R–R interval duration (RR, ms) was calculated. Spectral (frequency domain) analysis ECG waveform data were imported offline into Spike CED (version 6.0). The criteria for segment (90 s) selection for HRV analysis were stationarity and a lack of ectopic beats. Power spectra were obtained by Fourier transformation (size 256, Hanning window, giving a final frequency resolution of 0.04 Hz). Low- and high-frequency (LF and HF, respectively) powers were calculated within the frequency ranges of 0.2–0.7 Hz and 0.7–2.5 Hz, respectively, and the LF-to-HF ratio (LF/HF), a measure of the autonomic ‘balance’ (Friedman, 2007), was determined. An increase in LF/HF ratio indicates a rise in sympathetic activity (Pagani et al. 1986). HF power is exclusively under parasympathetic (vagal) control, and the peak frequency in the HF domain corresponds to the respiratory sinus arrhythmia (RSA; Stein et al. 1994; Porges et al. 2007). Temporal (time domain) analysis The root mean square of successive R–R interval differences (rMSSD, ms), which specifically quantifies parasympathetic activities (Stein et al. 1994), was calculated. Spontaneous baroreflex activation We used the sequence method to calculate spontaneous HR BRS (spontaneous BRS; Laude et al. 2004). Spontaneous BRS was calculated as the mean slope of R–R interval sequences for all sequences detected during 90 s segments of data. Pharmacological baroreflex activation The administration of nitroprusside (100 μg kg−1, i.v.) followed by phenylephrine (10 μg kg−1, i.v.) made it possible to evaluate the maximal BRR (maximal BRR in mmHg−1= 100 × (ΔHR/HR baseline)/ΔMBP]) and to generate baroreceptor function curves, by fitting a sigmoid logistic function to the data. The maximal (i.e. pharmacological maximal BRS) and rectilinear (pharmacological linear BRS) baroreflex slopes were calculated from the baroreceptor curves (Netzer et al. 2011). Animals were killed at the end of the procedures for cardiovascular parameter analyses by a lethal dose of anaesthesia (pentobarbital sodium, 120 mg kg−1, i.p.). All the procedures listed above were performed in each of the following experiments. Five series of experiments were performed on five different series of rats. Experiment 1: no treatment In this experiment, ND (n= 10) and D (n= 10) rats received no treatment. Experiment 2: chronic anxiolytic treatment Social defeat was performed from D1 to D4. Then ALZET osmotic pumps supplying vehicle (VEH) or chlordiazepoxide (CDZ; 10 mg kg−1 day−1) were implanted (Rivat et al. 2010) in ND (n= 7 each) and D (n= 7 and 8, respectively) rats on the morning of the day after completion of the social defeat (D5). Briefly, pumps filled with CDZ (ALZET 2ML1) were implanted subcutaneously on the back of the rats under light isoflurane anaesthesia. A small incision was made in the skin between the scapulae. Using a haemostat, a small pocket was formed by spreading the subcutaneous connective tissues apart. The pump was inserted into the pocket. The skin incision was closed with absorbable sutures. Therefore these treatments did not affect body weight before D5. The infusion of VEH or CDZ continued from D5 to D10, to prevent the development of the anxiety-like state (Rivat et al. 2010). At D10, we compared the effects of VEH and CDZ on physiological, behavioural and cardiovascular parameters. Experiment 3: acute pharmacological blockade of the DMH On D10, anaesthetized animals with pentobarbital sodium were placed in a stereotaxic frame, with the head fixed in the flat skull position. Microinjections of saline or muscimol (MUSC; 500 pmol in 0.1 μl) into the DMH were performed at the following coordinates: P 3.0, L 0.5 and V 8 mm from bregma (Netzer et al. 2011), in ND (n= 6 and 10, respectively) and D (n= 7 and 13, respectively) animals. Injections were made bilaterally to maximize the effect and because DMH control of HR has been shown to be assymetric (Xavier et al. 2009). We compared the effects of DMH saline and MUSC on cardiovascular parameters, and we expressed changes as variations from the baseline. Experiment 4: acute pharmacological blockade of NTS 5-HT3 receptors As described above, a micropipette filled with either saline or a selective 5-HT3 receptor antagonist (granisetron (GRANI) 250 pmol in 0.1 μl) was inserted into the NTS. Microinjections of saline or GRANI were performed at the level of the calamus scriptorius (L 0.5 and V 0.5 mm; Sévoz-Couche et al. 2003) of ND (n= 8 each) and D (n= 8 each) rats on D10. Injections were made bilaterally to maximize the effect (Sévoz-Couche et al. 2003). We compared the effects of NTS VEH and GRANI on cardiovascular parameters, and we expressed changes as variations from the baseline. Experiment 5: acute pharmacological blockade of peripheral and central 5-HT3 receptors GRANI is a 5-HT3 receptor antagonist known to cross the blood–brain barrier (Huang et al. 1998). Saline or GRANI (10 μg kg−1) was administered systemically (0.1 ml) in ND (n= 10 each) and D (n= 10 each) anaesthetized rats on D10. We compared the effects of i.v. VEH and GRANI on cardiovascular parameters, and we expressed changes as variations from the baseline. The effects of MUSC and GRANI lasted for at least 30 min (Sévoz-Couche et al. 2003; Netzer et al. 2011). HRV and spontaneous BRS parameters were analysed 20 min before and 10 min after treatments, from 90 s segments of recording. The pharmacological BRS was performed 5 min after the HRV and spontaneous BRS analyses, therefore 15 min before and 15 min after treatments. MUSC and sodium nitroprusside (Sigma Chemicals, St Louis, USA), phenylephrine hydrochloride (Merck Sharp and Dohme-Chibret, Paris, France) and GRANI (SmithKline-Beecham, Harlow, UK) were dissolved in saline. The pH of all solutions microinjected into the NTS was adjusted to 7.4. In experiments 3 and 4, microinjection sites were identified by the location of the micropipette track in 70 μm-thick sections of brain tissue previously fixed in 10% formalin solution and cryoprotected in 20% sucrose solution for 5 days. Only rats with the injection point correctly positioned in the DMH or NTS were considered for data analysis. In Experiment 1, a one-way (subjects) repeated (time)-measures ANOVA was used to compare body weights throughout the protocol, and a one-way (subjects) ANOVA was used to compare other behavioural, physiological and cardiovascular parameters. In Experiment 2, a two-way (subjects, treatments) repeated (time)-measures ANOVA was used to compare body weights throughout the protocol, and a two-way (subjects, treatments) ANOVA was used to compare the effects of VEH and treatments on other behavioural, physiological and cardiovascular parameters. In Experiments 3–5, a one-way (subjects) repeated (time)-measures ANOVA was used to compare body weights throughout the protocol, a one-way (subjects) ANOVA was used to compare time spent in the open arms of the elevated plus maze and adrenal gland weight, a two-way (subjects, treatments) ANOVA was used to compare the effects of VEH and treatments on cardiovascular parameters, and a paired Student's t test was used to compare cardiovascular parameters before and after treatment in the same animals. All the statistical results from the two-way ANOVA were given in Supplemental Tables 1–5. Bonferroni correction was applied to all ANOVAs, and results were considered significant if P < 0.05. Before the start of the social defeat procedure (Fig. 1A), D and ND animals had similar body weights (Fig. 1B). After social defeat sessions, D rats weighted less (−20%) than ND rats. This divergence began from the day after the first conditioning session (D2) and persisted until the end of the procedure (D10). Adrenal gland weight was higher (Fig. 1C) and time spent in the open arm was lower (Fig. 1D) in D animals, as previously reported (Rivat et al. 2010). We found no statistically significant difference in the total number of entries between ND and D rats (ND: 30.90 ± 2.99 and D: 27.70 ± 4.39, P= 0.07). Thus, the observed difference in time spent in the open arms between these two groups of rats was not due to a change in general activity. HR and MBP The mean R–R interval was significantly lower in D rats than in ND rats (Fig. 2Aa), corresponding to an increase in HR (345 ± 7 vs. 321 ± 3 bpm, respectively, P= 0.021). HR was positively correlated with adrenal gland weight in D animals (Fig. 2Ab). D and ND animals had similar basal MBP (D: 102 ± 3 vs. ND: 105 ± 2 mmHg, respectively, P= 0.68). Long-term consequences of the social defeat protocol for heart rate variability (HRV) in non-defeated (ND) and defeated (D) rats with no treatment A, representative R–R interval time series (Aa) showed that the mean R–R interval was lower (indicating an increase in heart rate (HR)) in D animals than in ND animals, and that fluctuations around the mean were much smaller than those in controls. The increase in HR seen in D rats was positively correlated with adrenal gland weight (Ab). B, frequency domain analysis of HRV. Analysis of the power spectra of R–R intervals (Ba) showed a lower high-frequency domain (HF) value in D rats, associated with an increase in low-frequency domain (LF) and LF/HF (Bb). Therefore, a decrease in parasympathetic tone was observed, together with an increase in sympathetic activity, in D rats. Data plots of all animals, lines are the means for D or ND animals. *P < 0.05 and ***P < 0.001 vs. ND rats. C, time domain analysis of HRV. The root mean square of successive R–R interval differences (rMSSD) was smaller for D than for ND rats (Ca). Modification in rMSSD was negatively correlated with adrenal gland weight (Cb). Data plots of all animals, lines are the means for D or ND animals. **P < 0.005 vs. ND rats. HRV We performed power spectral analysis on the ECG (Fig. 2Ba). Compared with ND animals, D rats had a reduced HF power associated with an increased LF power and LF/HF ratio (Fig. 2Bb). There was thus an increase in sympathetic tone associated with a decrease in parasympathetic tone in animals subjected to social defeat. The altered parasympathetic activity was confirmed by a reduction in rMSSD in D rats (Fig. 2Ca), which was negatively correlated with adrenal gland weight (Fig. 2Cb). Baroreflex measurements Spontaneous BRS was significantly lower in D than in ND animals (Fig. 3Aa), and was negatively correlated with adrenal gland weight (Fig. 3Ab). During the pharmacological induction of the baroreflex with nitroprusside followed by phenylephrine, the maximal BRR was lower in D (0.37 ± 0.04 mmHg−1) than in ND (0.62 ± 0.05 mmHg−1, P < 0.001) rats. Accordingly, the pharmacological maximal BRS slope calculated from the sigmoid baroreflex curves was lower in D rats (Fig. 3B, left), as was the pharmacological linear BRS (Fig. 3B, right). Values and statistics are given in Fig 3B (lower panel). Long-term consequences of the social defeat protocol for baroreflex parameters in non-defeated (ND) and defeated (D) rats with no treatment A, spontaneous baroreflex sensitivity (BRS), measured by the sequence method, was lower in D than in ND animals (Aa), and this decrease was inversely correlated with the development of an anxiety-like state (Ab). Data plots of all animals, lines are the means for D or ND rats. *P < 0.005 vs. ND intruders. B, the administration of nitroprusside followed by phenylephrine made it possible to generate baroreceptor function curves by fitting a sigmoid logistic function to the data (left). The maximal BRS calculated from the slope of these curves was lower in D than in ND rats. In the same manner, the linear BRS calculated from the linear part of the sigmoid curves (right) was lower in D rats. The values shown in the table are the means ± SEM for D and ND rats. To prevent the development of the anxiety-like state (Rivat et al. 2010), and to observe the effects of this prevention on cardiovascular parameters, an anxiolytic treatment was given after completion of the social defeat (D5). In the group of D rats, CDZ treatment maintained normal body weight gain (Fig. 4A), adrenal gland weight and behaviour in the plus maze (Fig. 4B), while no change was observed in ND animals. Effects of vehicle (VEH) and chlordiazepoxide (CDZ) treatment on physiological, behavioural and cardiovascular parameters in non-defeated (ND) and defeated (D) rats Compared with VEH, the anxiolytic treatment (10 mg kg−1 day−1) given at D5 (A, arrow) prevented the decrease in body weight gain (A), the increase in adrenal gland weight and the decrease in the time spent in open arms (B), the changes in frequency (Ca) and time (Cb) domain parameters for HRV, and the decrease in spontaneous (D) and pharmacological linear (E) BRS in D rats, but not in ND rats. B, box–Whisker graphs with minimum and maximum values, lines are the medians. **P < 0.005 and ***P < 0.001 vs. ND + VEH; §P < 0.05 and §§§P < 0.001 vs. D + VEH. C and D, data plots of all animals, lines are the means for D and ND rats. *P < 0.05 and **P < 0.005 vs. ND + VEH; §P < 0.05 and §§§P < 0.001 vs. D + VEH. HR HR was significantly higher in D than in ND treated with VEH (D + VEH: 354 ± 7 and ND + VEH: 320 ± 7 bpm, P= 0.021). Anxiolytic treatment reduced HR in D rats (D + CDZ: 321 ± 8 bpm, P= 0.006), whereas HR remained unaffected in ND animals (ND + CDZ: 320 ± 7 bpm, P= 0.91). HRV and baroreflex measurements LF and LF/HF were higher, and HF and rMSSD were lower in D than in ND rats with VEH (Fig. 4Ca and Cb). These alterations were suppressed by CDZ (Fig. 4Ca and Cb). The treatment had no effect in ND rats. The lower spontaneous BRS seen in D animals with VEH treatment was also suppressed with CDZ (Fig. 4D). CDZ did not affect spontaneous BRS in ND rats (Fig 4D). Similar results were obtained with pharmacological linear BRS (ND + VEH: −4.0 ± 0.2 bpm mmHg−1 vs. ND + CDZ: −3.5 ± 0.1 bpm mmHg−1, P= 0.67; D + VEH: −2.5 ± 0.3 bpm mmHg−1 vs. D + CDZ: −4.4 ± 0.4 bpm mmHg−1, P= 0.001; Fig. 4E). The DMH has been shown to be responsible for similar alterations in acute stress (Sévoz-Couche et al. 2003; Netzer et al. 2011). We therefore analysed the possible involvement of the DMH in this model of chronic stress. HR and MBP Unlike saline, the changes in HR (ΔHR/baseline HR) and MBP (ΔMBP/baseline MBP) after MUSC microinjection were greater in D rats than in ND animals (Fig. 5Aa and Ab). HR between-group differences in animals with saline (ND + DMH VEH: 315 ± 5 and D + DMH VEH: 349 ± 8 bpm, P= 0.004) were eliminated after MUSC (ND + DMH MUSC: 310 ± 7 and D + DMH MUSC: 290 ± 11 bpm, P= 0.75). Parameters returned to baseline after 10 min in D rats, but only after 2 min in ND rats. Effects of microinjection into the dorsomedial hypothalamus (DMH) of vehicle (VEH) or muscimol (MUSC) on cardiovascular parameters in non-defeated (ND) and defeated (D) rats A, MUSC induced larger reductions in heart rate (HR) and mean blood pressure (MBP) from baselines than saline in D but not in ND rats (Aa). Representative tracings of the effects of MUSC are shown in Ab. Box–Whisker graphs with minimum and maximum values, lines are the medians. §§§P < 0.001 vs. D + VEH. B–D, compared with VEH, DMH MUSC prevented the changes in frequency (Ba) and time (Bb) domain parameters for heart rate variability (HRV), spontaneous (C) and pharmacological linear (D) baroreflex sensitivity (BRS) observed in D rats, but had no effect on ND rats. Data plots of all animals, lines are the means for D and ND rats. *P < 0.05, **P < 0.005 and ***P < 0.001 vs. ND + VEH; §P < 0.05 and §§§P < 0.001 vs. D + VEH. HRV Compared with saline, while no change was observed in ND rats, MUSC prevented the changes in HRV in D rats (Fig. 5Ba and Bb). The same was observed when the comparisons were made in D rats before and after the MUSC injection (LF: 1.55 ± 0.07 vs. 0.77 ± 0.06 ms2, respectively, P < 0.001; HF: 5.46 ± 0.56 vs. 8.84 ± 0.64 ms2, respectively, P < 0.001; LF/HF: 0.17 ± 0.01 vs. 0.11 ± 0.01, respectively, P= 0.008; rMSSD: 1.02 ± 0.10 vs. 1.60 ± 0.12 ms, respectively, P < 0.001). Baroreflex measurements While no change in the spontaneous BRS was observed in ND rats, MUSC compared with saline restored the BRS in D rats (Fig. 5C). The same was observed when the comparison was made in D rats before and after the MUSC injection (0.87 ± 0.13 vs. 2.80 ± 0.28 bpm s−1, before and after MUSC, respectively, P < 0.001). While no change in linear BRS was observed in ND (ND + DMH VEH: −4.3 ± 0.2 bpm mmHg−1 vs. ND + DMH MUSC: −3.9 ± 0.1 bpm mmHg−1, P= 0.3) rats, MUSC compared with saline prevented the low linear BRS in D rats (D + DMH VEH: −2.0 ± 0.1 bpm mmHg−1 vs. D + DMH MUSC: −4.5 ± 0.2 bpm mmHg−1, P= 0.005; Fig. 5D). The same was observed when the comparison was made in D rats before and after the MUSC injection (−2.7 ± 0.2 vs.−4.5 ± 0.2 bpm mmHg−1, respectively, P= 0.005). Downstream from the DMH, presynaptic 5-HT3 receptors in the NTS are responsible for decreasing the baroreflex in conditions of acute stress (Sévoz-Couche et al. 2003; Netzer et al. 2011). We therefore analysed the possible role of these receptors in our model of chronic stress. HR and MBP The microinjection of GRANI into the NTS, unlike that of saline, induced a greater reduction in MBP in D than in ND rats, but had no effect on HR in either group of rats (Fig. 6Aa and Ab). Parameters returned to baseline after 10 min in D rats, but only after 2 min in ND rats. Effects of microinjection into the nucleus tractus solitarii (NTS) of vehicle (VEH) or granisetron (GRANI) on cardiovascular parameters in defeated (D) and non-defeated (ND) rats A, GRANI injection into the NTS induced a larger decrease in mean blood pressure (MBP) but not in heart rate (HR) than saline in D rats, but had no effect on either of these parameters in ND (Aa). Representative tracings of the effects of GRANI injection into the NTS are given in Ab. Box–Whisker graphs with minimum and maximum values, lines are the medians. §P < 0.05 vs. D + VEH. B, compared with VEH, the injection of GRANI into the NTS abolished the reduction in high-frequency domain (HF) but not the increase in low-frequency domain (LF)/HF in D rats (Ba), and had no effect in ND rats (Ba), suggesting that GRANI reversed the decrease in parasympathetic activity but not the increase in sympathetic activity. This treatment also eliminated the decrease in time domain HRV analysis (Bb) normally induced in D rats, and had no effect on ND rats. Data plots of all animals, lines are the means for D and ND rats. *P < 0.05, **P < 0.005 and ***P < 0.001 vs. ND + VEH; §§P < 0.005 and §§§P < 0.001 vs. D + VEH. C and D, the low spontaneous baroreflex sensitivity (BRS) (C) and pharmacological linear (D) BRS in D rats with VEH was prevented in D rats with i.v. GRANI, and was unchanged in ND rats. ***P < 0.001 vs. ND + VEH; §§§P < 0.001 vs. D + VEH. HRV While HRV parameters were unchanged in ND rats, GRANI compared with saline restored HF and rMSSD in D animals, but not LF and LF/HF (Fig. 6Ba and Bb). The same was observed when the comparisons were made in D rats before and after the GRANI injection (HF: 5.40 ± 0.49 vs. 7.66 ± 0.70 ms2, respectively, P= 0.036; LF: 1.12 ± 0.09 vs. 1.03 ± 0.11 ms2, respectively, P= 0.40; LF/HF: 0.18 ± 0.01 vs. 0.14 ± 0.01, respectively, P= 0.09; rMSSD: 1.10 ± 0.11 vs. 2.10 ± 0.22 ms, respectively, P= 0.004). Baroreflex measurements While no change in the spontaneous BRS was observed in ND animals, GRANI" @default.
• W1501888346 created "2016-06-24" @default.
• W1501888346 creator A5030781097 @default.
• W1501888346 creator A5050432559 @default.
• W1501888346 creator A5059196077 @default.
• W1501888346 creator A5059739845 @default.
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• W1501888346 date "2013-02-11" @default.
• W1501888346 modified "2023-10-18" @default.
• W1501888346 title "Involvement of the dorsomedial hypothalamus and the nucleus tractus solitarii in chronic cardiovascular changes associated with anxiety in rats" @default.
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