It has been demonstrated that 5-CT administration causes hypothermia in guinea-pigs (Hagan et al, 2000) and mice (Guscott et al., 2003) by activation of 5-HT₇ receptors. Thus at least in these species hypothermia does not involve other 5-HT receptors, especially the 5-HT₁ receptor subtype, for which 5-CT also has high affinity (see Hoyer et al., 2002). Recently, central 5-HT₇ receptors have been demonstrated to play an excitatory role in the micturition reflex (Read et al., 2003). Thus, the present experiments were carried out to investigate the possibility that centrally applied 5-CT could evoke the micturition reflex.

Experiments were performed in spontaneously-breathing female Sprague Dawley rats (200-270g) anaesthetized with urethane (1.2 g kg^-1; i.v.). Depth of anaesthesia was assessed by the stability of blood pressure and heart rate, and by an absence of hind limb withdrawal in response to paw pinch. If needed, supplementary doses of urethane were given (0.1 g kg^-1, i.v.). "Micturition reflexes" were evoked by distension of the urinary bladder with saline infusion (0. 1 ml min^-1; see Read et al., 2003). Drug or saline were administered i.c.v and changes evoked 3 min after drug or saline administration were compared with saline controls by unpaired Student's t-test. All values are means ± s.e. mean.

5-CT (3 nmol kg^-1; n=6) caused a non-significant increase in the pressure threshold by 36 ± 15%. However, 10 nmol kg^-1 caused significant (P <0.05) decreases in volume and pressure threshold by 33 ± 18% and 46 ± 8% respectively in 3 rats yet blocked the reflex in the remaining 3 rats. In the presence of the 5-HT_1B/1D receptor antagonist GR127935 (100 µg kg^-1; n = 6) 5-CT (10 nmol kg^-1) caused a significant reduction in the volume threshold by 60 ± 12 % and evoked spontaneous bladder contractions. GR127935 alone caused a significant increase in the volume threshold by 94 ± 35%. Both the 5-HT_1B/1D receptor agonist sumatriptan (10 µg kg^-1, n=5) and 5-HT_1B receptor agonist CP-93,129 (100 µg kg^-1, n=5) abolished the micturition reflex in 3 out of 5 and 5 out of 6 rats, respectively.

The present data suggest that the affinity of 5-CT for 5-HT_1B receptors interferes with the expected excitatory action of 5-CT on the bladder reflex through activation of 5-HT₇ receptors. The data also suggested these receptors may be involved in the micturition reflex. However, both GR127935 and 5-CT have good affinity for the 5-HT_1A receptor and this receptor is also involved initiation of the micturition reflex (Conley et al., 2001). In conclusion, the use of 5-CT to study the role of 5-HT₇ receptors in micturition is complicated by the fact that 5-HT₁ receptor subtypes also have a role in this reflex.

Conley R.K. et al., (2001) Br. J. Pharmacol. 133, 61-72.
Hagan, J.J. et al., (2000) Br. J. Pharmacol. 130, 539-548.
Hoyer, D et al., (2002) Pharmacol. Biochem. Behav. 71, 533-544.
Guscott, M.R. et al., (2003) Neuropharmacol. 44, 1031-1037.

K.E Read is a BBSRC CASE student with GSK.