Skinner, Matthew Richard Alistair; (1999) The role of 5-hydroxytyptamine1A receptors in the control of cardiorespiratory reflexes. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The work carried out in this thesis examines the modulatory role of central 5-HT1A receptors on the cardiorespiratory responses evoked by stimulating baroreceptor, chemoreceptor and cardiopulmonary receptor afferents. Experiments were performed using spontaneously breathing male rabbits anaesthetised with urethane. The animals were instrumented to allow continuous recordings of arterial blood pressure, heart rate, ECG, renal and phrenic nerve activity. Aortic baroreceptor afferents were activated by electrical stimulation of the left aortic nerve. Carotid chemoreceptor afferents were stimulated by close arterial injection of sodium cyanide into the left lingual artery. Cardiopulmonary afferents were stimulated by bolus injections of phenylbiguanide into the right atrium. Intracisternal administration of the 5-HT1A receptor partial agonist buspirone had significant effects on baseline cardiorespiratory parameters. In addition, intracisternal administration of buspirone potentiated the reflex vagal bradycardias evoked by stimulating baroreceptor, chemoreceptor and cardiopulmonary afferents. These effects could be attenuated by intravenous pre-treatment with the selective 5-HT1A receptor antagonist WAY-100635. This confirmed that the modulatory effects of buspirone are due to selective agonist effects at 5-HT1A receptors. In most cases, the same dose of buspirone given intravenously caused much smaller potentiating effects, thus suggesting that buspirone was acting at a site within the central nervous system. Intracisternal administration of WAY-100635 attenuated the reflex bradycardias evoked by stimulating baroreceptor and cardiopulmonary receptor afferents whilst intravenous administration of WAY-100635 had no effect. These results demonstrate that in the urethane-anaesthetised rabbit, central 5-HT1A receptors tonically modulate reflex cardiac vagal outflow. Experiments in which the dye, Pontamine sky blue, was injected intracisternally suggests that the most likely site of action of the 5-HT1A receptor ligands is at the level of the medulla oblongata.

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