Rostral cuneiform nucleus and the defence reaction: Direct and indirect midbrain–medullary 5‐HT mechanisms in baroreflex inhibition

Background and Purpose Activation of the defence reaction inhibits the baroreflex response via the intermediate rostro‐ventromedial medulla (B3 raphé) and nucleus tractus solitarius (NTS). Our aim was to determine whether and how baroreflex inhibition, induced by the disinhibition of the rostral cuneiform nucleus (part of the defence pathway), involves 5‐HT neurons in B3 and 5‐HT 3 receptors in the NTS. Experimental Approach We performed immunohistochemistry and anatomical experiments to determine whether raphé 5‐HT cells expressing Fos were directly targeted by the rostral cuneiform nucleus. The effect of blocking raphé 5‐HT neurotransmission and NTS 5‐HT 3 receptors on cuneiform‐induced inhibition of the baroreflex cardiac response were also analysed. Key Results Bicuculline, microinjected into the rostral cuneiform nucleus, induced an increase of double‐labelled Fos‐5‐HT‐IR cells in both the lateral paragigantocellular nucleus (LPGi) and raphé magnus. The anterograde tracer Phaseolus vulgaris leucoaggutinin injected into the rostral cuneiform nucleus revealed a dense projection to the LPGi but not raphé magnus. Cuneiform‐induced baroreflex inhibition was prevented by B3 injection of 8‐OH‐DPAT, a selective 5‐HT 1A receptor agonist. Cuneiform disinhibition also failed to inhibit the baroreflex bradycardia after NTS microinjection of the 5‐HT 3 receptor antagonist granisetron and in 5‐HT 3 receptor knockout mice. Conclusion and Implications The rostral cuneiform nucleus participates in the defence inhibition of the baroreflex bradycardia via direct activation of the LPGi and via a projection to the raphé magnus to activate NTS 5‐HT 3 receptors and inhibit second‐order baroreflex neurons. These data bring new insights in primary and secondary mechanisms involved in vital baroreflex prevention during stress.