Different stressful conditions elicit a typical behavior called the defense reaction. Our aim was to determine whether 5-HT3 receptors in the nucleus tractus solitarius (NTS) are involved in 1) the inhibition of the baroreflex bradycardia and 2) the rise in blood pressure, which are known to occur during the defense reaction. In urethane-anesthetized rats, the defense reaction was elicited by electrical stimulation of the dorsomedial nucleus of the hypothalamus (DMH) or the dorsal part of the periaqueductal gray (dPAG). Direct electrical stimulation of the aortic depressor nerve was used to trigger the typical baroreflex responses. Aortic stimulation at high (100-150 microA) and low (50-90 microA) intensity produced a decrease in heart rate of -39 to -44% (relative to baseline, Group 1 responses, n = 113) and -19 to -24% (Group 2 responses, n = 43), respectively. In spontaneously breathing rats, Group 1 and Group 2 bradycardiac responses were inhibited during DMH (-75 +/- 4% and -96 +/- 4%, n = 38 and n = 11, respectively), as well as dPAG (-81 +/- 3% and -95 +/- 4%, n = 36 and n = 10, respectively) stimulation. The aortic baroreflex bradycardia was hardly affected by DMH or dPAG stimulation when bicuculline (5 pmol), a specific GABAA receptor antagonist, had previously been microinjected into the NTS. Likewise, NTS microinjections of granisetron, a specific 5-HT3 receptor antagonist, prevented, in a dose-dependent manner, the baroreflex bradycardia inhibition. In addition, intra-NTS granisetron did not affect the rise in blood pressure induced by either site stimulation. These data show that 5-HT3 receptors in the NTS are involved in the GABAergic inhibition of the aortic baroreflex bradycardia, but not in the rise in blood pressure, occurring during the defense reaction elicited by DMH or dPAG stimulation.
Key points• 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-HT 3 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-HT 3 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. Abbreviations BP, blood pressure; BRR, cardiac baroreflex response; BRS, baroreflex sensitivity; CDZ, chlordiazepoxide; D, defeated rats; DMH, dorsomedial nucleus of the hypothalamus; GRANI, granisetron; HF, high-frequency domain; HR, heart rate; HRV, heart rate variability; LF, low-frequency domain; MBP, mean blood pressure; MUSC, muscimol; ND, non-defeated rats; NTS, nucleus tractus solitarii; rMSSD, root mean square of successive R-R interval differences; RSA, respiratory sinus arrhythmia; VEH, vehicle.
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