The role of central 5-hydroxytryptamine (5-HT, serotonin) receptors in the control of micturition.

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-HT(7), 5-HT(2) and 5-HT(3) 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-HT(7) 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-HT(7) 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-HT(7) receptor pathway. Neither receptor seems to play a role in the control of the urethra. Regarding 5-HT(2) 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 5HT(3) 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.