¹Department of Pharmacology, University College London, Hampstead Campus, Rowland Hill Street, London NW3 2PF

Correspondence: Andrew G. Ramage, E-mail: a.ramage@ucl.ac.uk

Abstract

At present the most investigated 5-HT receptor that has been shown to play a role in the control of micturition is the 5-HT_1A receptor followed by 5-HT₇, 5-HT₂ and 5-HT₃ receptors. Most experiments focus on the control these receptors have on the parasympathetic outflow to the bladder and the somatic outflow to the external urethral sphincter (EUS) in the rat. Furthermore, 5-HT_1A and 5-HT₇ receptors have been identified as having an excitatory physiological role in the control of bladder function. 5-HT_1A receptors act, at least in the rat, at both a spinal (probably a heteroreceptor) and supraspinal (probably an autoreceptor) level, while 5-HT₇ receptors only act at a supraspinal level. Additionally, in the rat, 5-HT administered at a spinal or supraspinal site has an excitatory action, although earlier experiments have shown that activating 5-HT-containing brain areas causes inhibition of the bladder. Recent experiments have also indicated that blockade of the 5-HT_1A receptor pathway shows rapid tolerance. However, no data exist for the development of tolerance for the 5-HT₇ receptor pathway. Neither receptor seems to play a role in the control of the urethra. Regarding 5-HT₂ receptors, activation of this receptor subtype inhibits micturition, and this inhibitory action may occur at a spinal, supraspinal or both levels. Although no physiological role for 5-HT_2C receptors can yet be identified, 5-HT_2C receptors have been implicated in the proposed supraspinal tonically active 5-HT_1A autoreceptor (negative feedback) pathway. This proposition reconciles the data that central 5-HT-containing pathways are inhibitory to micturition, while 5-HT_1A receptors, although inhibitory to adenylyl cyclase, have an excitatory function. This is because activation of 5-HT_1A autoreceptors reduces the release of 5-HT thus reducing the activation of the 5-HT_2C receptors, which are inhibitory in the control of micturition (disinhibition). Furthermore, 5-HT_2A receptors in the rat and 5-HT_2C receptors in the guinea pig cause activation of the EUS. In this respect, 5-ht_5A receptors have also been identified in Onuf's nucleus, the site of somatic motoneurones controlling this sphincter. In the cat there is very little evidence to indicate that 5-HT receptors are involved in micturition except under pathological conditions in which activation of 5-HT_1A receptors causes inhibition of micturition. Interestingly, under such conditions 5-HT_1A receptors cause excitation of the EUS. Nevertheless, spinal 5HT₃ receptors have been implicated in the physiological control of micturition in the cat, but not yet in the rat. Overall, the data support the view that 5-HT receptors are important in the control of micturition. However, many more studies are required to fully understand these roles and why there are such species differences.