Considering the relatively small number (thousands cf. billions) of 5 HT (serotonin) containing neurones that are found in the brain it is surprising that 5 HT is involved in so many functions. The function of 5-HT in central cardiovascular respiratory regulation in a sense has been overlooked and even here 5-HT may be considered to play “third fiddle” to amino acid and adrenergic transmission. This is not surprising as when David Jordan and I started our collaboration in the mid 80s the view was that “alteration in … cerebral 5-HT systems can alter BP but unfortunately … the role of 5-HT in BP regulation can only be made with caution”(Kuhn et al. 1980 Hypertension 2:243). The system needed a drug similar to clonidine in the adrenergic system. For the 5-HT system this turned out to be 8-OH-DPAT, a simplified ergot congener, which was selective for 5 HT_1A receptors (there are 14 receptor subtypes). The observations that 8-OH-DPAT caused a fall BP and a very large increase in vagal drive to the heart quickly triggered our collaboration. Initially, this led to the demonstration that 5-HT_1A receptors, at the level of the nucleus ambiguus, are involved in the genesis of cardiopulmonary afferent evoked vagal bradycardia. The role of 5-HT_1A receptors in other reflex bradycardias shows a degree of species variation (see Jordan, 2005). In contrast there is no evidence for a role for 5 HT_1A (sympathoinhibitory) or 5-HT₂ (sympathoexcitatory) receptors, in the sympathetic regulation of the heart (see Ramage, 2001). Interestingly, activation of central 5-HT₂ receptors causes vasopressin release and this has been suggested to play an important role in blood volume regulation. In this respect chronic treatment with a 5-HT₂ receptor antagonist prevents the development of DOCA-salt hypertension, which is consistent with the view that this form of hypertension requires the release of vasopressin. This system may also be involved in stress hypertension. The involvement of 5-HT₃ receptors in cardiovascular regulation was also studied. This receptor is found in a very high density in the nucleus tractus solitarius (NTS), the site of termination of baroreceptor and other visceral afferents (Jordan & Spyer, 1986), and the dorsal vagal nucleus (DVN). Within the DVN and NTS ionophoretic application of the highly selective 5-HT₃ receptor agonist phenylbiguanide (PBG) excited most neurones tested, and this excitation was blocked by the antagonist granisetron. Intracellular recording (in vivo) showed that PBG application caused little change in the membrane potential although firing rate increased, while the glutamate receptor agonist DLH caused membrane depolarization with increased firing. This indicates that neuronal excitation by 5-HT₃ receptors is indirect and is consistent with the view that these receptors are mainly on afferent terminals. Further experiments demonstrated that both in the DVN and NTS, activation of 5-HT₃ receptors causes the release of glutamate which acts on NMDA and/or kainate receptors to activate these neurones (Jeggo et al. 2005). It was suggested that the source of glutamate could also be glial cells in the NTS (Llewellyn-Smith et al. 2004). More recently 5-HT₇ receptor blockade was shown to abolish all reflex (cardiopulmonary, baroreceptor and chemoreceptor) evoked increases in vagal drive to the heart in both anaesthetized and conscious rats (Kellett et al. 2005). This is believed to occur at the level of the NTS (Oskutyte et al. 2008). In addition, depletion of 5-HT with p-CPA causes an increase in BP in awake rats and attenuates the baroreflex gain in both awake and anaesthetized rats. In conclusion it can be stated that 5-HT is released in the reflex activation of cardiac vagal pathways and that activation of 5-HT₇ receptors is essential for the mediation of such effects. However the role for 5 HT_1A and 5 HT₃ receptors is far less clear. In blood pressure regulation there is an indication that 5-HT pathways are involved, at least in hypertension, especially that which involves vasopressin release.