Secker, Alexandra Gray; (2004) An investigation into the effects of acute and chronic blockade of 5-HT1A receptors involved in the control of micturition. Doctoral thesis (Ph.D.), University College London (United Kingdom).

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Abstract

The storage and periodic elimination of urine (micturition) is dependent upon a complex neural co-ordination of activities in the bladder and urethra. 5-HT1A receptors have been suggested to be involved in the central control of micturition, and considered a potential therapeutic target, since 5-HT1A receptor antagonists acutely inhibit micturition in anaesthetized rats. However, recent studies examining 5-HT-containing neuronal control in the field of affective disorders, have shown 5-HT1A receptors to be highly labile and easily desensitized, suggesting that the long-term effects of chronic administration of 5-HT receptor ligands may differ from those observed after acute administration. Therefore, the present studies initially characterized the acute and chronic effects of 5-HT1A receptor antagonists on micturition in urethane-anaesthetized and conscious female rats. Further characterisation of the effects of chronic administration of a 5-HT1A receptor antagonist on supraspinal 5-HT control was obtained using radiotelemetry and quantitative autoradiography studies. The 5-HT1A receptor antagonist, WAY-100635, significantly suppressed micturition in a dose dependent manner after acute intracerebroventricular and intrathecal (L6/S1) administration in anaesthetized rats, thus confirming the involvement of 5-HT1A receptors in the control of micturition, at both supraspinal and lumbosacral spinal levels. A similar suppression of micturition was observed in conscious rats after acute intravenous (i.v.) administration (3 h infusion) of WAY-100635 and robalzotan (NAD-299, a structurally distinct 5-HT1A receptor antagonist). However, by the fourth day of chronic i.v. administration (via osmotic minipump) of WAY-100635 or robalzotan, neither 5-HT1A receptor antagonist had any significant effect on conscious micturition measurements. This observation of a lack of effect of 5-HT1A receptor antagonists on micturition after chronic treatment was confirmed using anaesthetized cystometry studies in chronically treated rats, thus suggesting that these animals had developed 'tolerance' to 5-HT1A receptor antagonists after chronic administration. Further characterization of the onset of the 'tolerance' phenomenon was obtained in rats using radiotelemetry measurements of bladder activity and a subcutaneous injectable pump for i.v. administration of WAY-100635, which showed that 'tolerance' occurs within 24 hours of administration. Since supraspinal 5-HT receptors, and 5-HT1A receptors in particular, are highly labile, it is possible that the observed 'tolerance' phenomenon resulted from a change in the density of these receptors after chronic administration. This was investigated using quantitative autoradiography, which showed that chronic WAY-100635 administration caused almost a 50% increase in the level of [3H] WAY-100635 binding in various brain regions including the raphe nuclei. 5-HT1A receptor levels were still raised after a 6-day wash-out period, thus confirming this 'tolerance' phenomenon to be long lasting. Changes in the levels of 5-HT1B 1D receptors and the 5-HT transporter (5-HTT) were also observed, thus highlighting the complex level of interaction between serotonin receptors involved in supraspinal 5-HT-containing neuronal control.These studies indicate that the chronic administration of 5-HT1A receptor antagonists results in the onset of tolerance towards the ligands, which is characterized by an upregulation of 5-HT1A receptors in various brain regions. Furthermore, additional changes in 5-HT1B 1D receptors and 5-HTT levels, suggest a high level of complexity in supraspinal 5-HT control. Thus, it appears that treating overactive bladder with long-term administration of 5-HT1A receptor antagonists is unlikely to be clinically efficacious, and therefore has little therapeutic potential.

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