Involvement of the dorsomedial hypothalamus and the nucleus tractus solitarii in chronic cardiovascular changes associated with anxiety in rats

Authors


C. Sévoz-Couche: CR-ICM, UPMC/INSERM, UMR-S 975, CNRS UMR 7225, Faculté de médecine UPMC, Site Pitie-Salpêtrière, 91 bd de l’Hôpital, Paris F-75013, France. Email: caroline.sevoz-couche@upmc.fr

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-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.

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