Read, Katharine Emma; (2004) The role of 5-hydroxytryptamine receptors in the control of micturition. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Central 5-HT containing neurones, via activation of 5-HT1A receptors, play an important role in the facilitation of parasympathetic outflow to the bladder. However, there are no reports on the role of 5-HT7 receptors in the reflex control of micturition, even though many non-selective 5-HT receptor ligands have been shown to bind to 5-HT7 receptors, and have both excitatory and inhibitory effects on micturition. Using selective 5-HTv receptor antagonists SB-269970 and SB-656104, this work demonstrates an important physiological role for supraspinal, but not spinal, 5-HT7 receptors in the control of micturition in the urethane anaesthetized rat. Blocking supraspinal 5-HT7 receptors, micturition is inhibited, with an increased volume and pressure required in the bladder to initiate micturition, but no significant effects on urethral function. In addition these data show that central administration of the 5-HT2C receptor antagonist mesulergine, which binds with high affinity to the 5-HT7 receptor, also inhibits the micturition reflex, but only at a high dose. However, these data do not support a role for the 5-HT2C receptor in the control of micturition, as demonstrated using the selective 5-HT2C receptor antagonist SB-243213. There are no selective agonists for the 5-HT7 receptor. However, 5-CT can be used to activate 5-HT7 receptors in mice and guinea pigs to induce hypothermia, which can be inhibited by selective 5-HT7 receptor antagonist SB-269970, but not by WAY-100635 or GR127935. Therefore, central administration of 5-CT was used to facilitate micturition, via 5-HT7 receptor activation, in the anaesthetized rat. These data demonstrate that facilitation of micturition was possible using 5-CT, but only in the presence of the selective 5-HT1B/1D receptor antagonist GR 127935. Therefore these data further support a facilitatory role for the 5-HT7 receptor, but also an inhibitory role for 5-HT1B/1D receptor in the control of micturition, which was further confirmed using selective 5-HT1B/1D receptor agonist sumatriptan and 5-HT1B receptor agonist CP93,129, which both inhibited micturition. Overall this thesis further characterises the functional role of 5-HT receptors in the control of micturition.

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