Jeggo, Ross David; (2003) 5-HT receptors of brainstem cardio-respiratory neurones. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Experiments were performed on anaesthetized rats and cats to examine the effects of cardiopulmonary afferent activation on neuronal activity in the nucleus ambiguus (NA) and the nucleus tractus solitarius (NTS). Furthermore, the role of 5-HT1B/1D and 5-HT3 receptors in the NTS was studied in rats including examinations into their role on identified inputs, such as cardiopulmonary afferent activation. Anaesthetized animals were instrumented to allow recording of cardiovascular and respiratory variables, neurones were recorded using glass microelectrodes and the central administration of compounds was carried out using ionophoresis. Cardiopulmonary afferents were activated by right atrial injections of the 5-HT3 receptor agonist phenylbiguanide (PBG), and NA and NTS neurones were identified by a combination of their response to vagus nerve stimulation and histological localisation. The majority of B-fibre cardiac vagal preganglionic neurones (CVPNs) of the NA were excited by right atrial PBG administration and this excitation was maintained in the absence of respiratory drive. The majority of NTS neurones recorded responded to right atrial PBG, with the highest proportions of these neurones (70%) excited by this stimulus. The 5-HT1B/1D receptor agonist sumatriptan decreased the activity of the majority of NTS neurones recorded and also attenuated both the vagal- evoked and cardiopulmonary afferent-evoked activation of NTS neurones. In contrast, the 5-HT1B receptor agonist CP-93,129 increased the activity of the majority of NTS neurones, and excited both vagal-evoked and cardiopulmonary afferent-evoked activation. The inhibitory action of sumatriptan on neuronal activity was attenuated in the majority of neurones in the presence of the 5-HT1D receptor antagonist ketanserin, whilst it was potentiated in the majority of neurones in the presence of the 5-HT1B receptor antagonist GR55562B. Ionophoretic PBG increased the activity of the majority of NTS neurones and potentiated the vagal-evoked and cardiopulmonary afferent-evoked activation of neurones. The 5-HT3 receptor antagonists granisetron and ondansetron and the NMDA receptor antagonist AP-5 attenuated this PBG- evoked increase in activity in the majority of neurones. Granisetron and AP-5 also attenuated the cardiopulmonary afferent-evoked activation of the majority of NTS neurones. These data suggest that the cardiopulmonary reflex-evoked bradycardia is mediated in part by B-fibre CVPNs in the NA. In addition, 5-HT1B and 5-HT3 receptors play an excitatory role, whilst 5-HT1D receptors play an inhibitory role in the functioning of the NTS. Furthermore, the excitatory action of 5-HT3 receptors is mediated in part via the release of glutamate, acting at NMDA receptors, and these 5-HT3 receptors are tonically active during cardiopulmonary afferent transmission in the NTS.

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