Vagal control of the heart: central serotonergic (5-HT) mechanisms

Cardiac vagal preganglionic neurones (CVPNs) are located within the dorsal vagal nucleus (DVN) and the nucleus ambiguus (nA). In mammals, CVPNs within the nA have small myelinated axons and mediate major chronotropic effects, those in the DVN have non-myelinated axons and mediate smaller chronotropic, dromotropic and inotropic effects. Numerous studies demonstrate important influences of serotonin (5-HT) at multiple sites controlling autonomic outflows including the nucleus tractus solitarius (NTS) where cardiorespiratory afferent fibres terminate, and the CVPNs and rostral ventrolateral medulla (RVLM), the location of sympathetic premotor neurones. We have demonstrated roles for some of the numerous 5-HT receptor subtypes (5-HT1, 5-HT2, 5-HT3, 5-HT4 and 5-HT7) in brainstem regions involved in cardiac control. Intracisternal application of selective ligands was used to study the effect of 5-HT receptors on heart rate and its reflex control. Further electrophysiological studies were also carried out to delineate their location and the mechanisms of action of these ligands. Blocking 5-HT1A receptors attenuated bradycardias evoked by stimulating baroreceptor and cardiopulmonary afferents but not arterial chemoreceptors, whereas antagonizing 5-HT7 receptors markedly attenuated all these reflex bradycardias. Within the DVN, nA and NTS, activation of 5-HT1A receptors could excite or inhibit neurones. In the NTS 5-HT2 receptors also had variable effects; 5-HT2B receptors excite and 5-HT2C receptors inhibit. Antagonism of 5-HT3 receptors attenuated upper airway and cardiopulmonary reflex bradycardias; this is compatible with data showing that 5-HT3 receptors excite DVN and NTS neurones by a glutamate-dependent mechanism. The origin of the glutamate (neuronal or glial) remains unresolved but glia are a possibility as barorecptor-sensitive NTS neurones receive few direct 5-HT-containing synaptic contacts. Thus, 5-HT plays a critical role in the control of vagal outflow to the heart; however, why so many different receptors are involved, and their relative functional roles, remains unresolved.