Evidence that central 5-HT1A receptors control micturition at both a supraspinal and sacral spinal sites in female urethane anaesthetised rats A.G.Secker, S.L.Westbrook* & A.G.Ramage. Department of Pharmacology, UCL, Royal Free Campus, London NW3 2PF and *Discovery Biology, Pfizer Ltd, Kent. CT13 9NJ.

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Central 5-HT_1A receptors have been shown to be involved in the control of micturition in anaesthetised rats (Testa et al., 1999; Conley et al., 2001). This has been suggested to be at a spinal site (Kakizaki et al., 2001) although supraspinal sites have not been ruled out. Therefore the present experiments examine the role of both supraspinal and spinal 5-HT_1A receptors in the micturition reflex, by comparing the effects of the 5-HT_1A receptor antagonist WAY-100635 (Forster et al, 1995) given i.c.v. with those of intrathecal (i.t.) administration at the thoracic T5/6 and sacral L6/S1 level on the onset time for suppression of bladder contractions.

Experiments were carried out in spontaneously breathing female Sprague Dawley rats (200-280g) anaesthetised with urethane (1.2 g kg^-1 i.v.) with initial surgery carried out under isoflurane anaesthesia. Animals were maintained between 36.5 - 37.5oC and blood gas levels were monitored. The vesico-urethral junction was blocked non-surgically to allow simultaneous measurement of both bladder and urethral pressures (see Conley et al., 2001). Isovolumetric 'micturition reflexes' were evoked by infusing saline (0.05 ml min^-1) into the closed bladder. The external urethral sphincter EMG (EUS-EMG) activity, BP and HR were also measured. I.c.v. and i.t. injections were administered in a 5µl volume, followed by a 5µl saline flush for i.t. injections. WAY-100635 was administered at the start of a bladder contraction/micturition reflex and changes compared with vehicle controls by unpaired Student's t-test. All values are means ± s.e.mean.

WAY-100635 i.c.v. (1,10 & 100 µg kg ^-1, n = 5) dose dependently and significantly (P<0.05) suppressed isovolumetric bladder contractions for 259 ± 86s, 526 ± 114s and 739 ± 176s respectively, with a mean onset time of 76, 65 and 36s. Thoracic i.t. administration (10 µg kg^-1, n = 4) had an onset time of 375 ± 74s, whereas L6/S1 i.t. administration (10 µg kg^-1,n = 5) caused an immediate suppression. Interestingly, a second dose of WAY-100635 (10 µg kg^-1, n = 5) both i.c.v. and i.t. (L6/S1) was only 39% (567 ± 117s to 234 ± 82s) and 26% (823 ± 174s to 217 ± 134s) as effective as the initial dose at suppressing bladder contractions. WAY-100635 (1, 10 & 100 µg kg^-1, n = 5) had no significant effect on the urethral responses during micturition.

These data demonstrate that central 5-HT_1A receptors at both supraspinal and spinal sites are involved in the control of micturition at the level of the bladder but not at the level of urethra. Further, the data suggests that the action of WAY?100635 on the reflex control of the bladder shows rapid tolerance at both sites of action.

Conley, R.K. et al. (2001) Br. J. Pharmacol., 133, 61-72.
orster, E.A. et al. (1995) Eur. J. Pharmacol., 281, 81-88.
Kakizaki, H. et al. (2001) Am. J. Physiol. 280, R1407-R1413.
Testa, R. et al(1999) J. Pharmacol. Exp. Ther. 290, 1258-69.

AGS is a MRC CASE student with Pfizer Ltd.