Effects of NAD-299, a new, highly selective 5-HT1A receptor antagonist, on bladder function in rats

5-HT is involved in micturition control. In the rat, stimulation of the 5-HT1A receptor excites, whereas 5-HT1A receptor antagonism inhibits micturition. The present study examined the effects of a new, highly selective, 5-HT1A receptor antagonist, NAD-299, on micturition in rats. Comparisons were made with WAY100635, a well-characterised antagonist. at the 5-HT1A receptor. Female Sprague-Dawley rats, conscious or anaesthetised, were used for cystometric studies. Intravenous (i.v.), intraarterial (i.a.), intrathecal (i.t.) or intracerebroventricular (i.c.v.) catheters were implanted for drug administration. In vitro, rat bladder strips were contracted by carbachol or electrical stimulation of nerves. The effects of NAD-299, WAY100635 and 8-hydroxy-2-(di-n-propyl-amino)tetralin (8-OH-DPAT, a 5-HT1A receptor agonist) on cystometric parameters and contraction of bladder strips were recorded. In conscious rats, i.v. NAD-299 and WAY100635 at 1 mumol kg(-1) increased bladder capacity (24 +/- 13% and 27 +/- 19% respectively) and decreased micturition pressure (16 +/- 8% and 12 +/- 10% respectively). Given i.a., 5-HT 0.25 mumol kg(-1) and 8-OH-DPAT 0.37 mumol kg(-1) stimulated micturition. The effect of 8-OH-DPAT, but not those of 5-HT, was blocked by i.a. NAD-299. 8-OH-DPAT 0.03 mumol given i.t. or i.c.v. stimulated micturition, an effect blocked by WAY100635 0.1 mumol, given i.t or i.c.v. NAD-299 or WAY100635 (0.1 mumol i.t.) were without significant effects, but given i.c.v. at 0.1 mumol both drugs increased bladder capacity (34 +/- 12% and 22 +/- 13% respectively). Neither NAD-299 nor WAY100635- up to 10(-5) M had effects on electrically- or carbachol-induced contractions of rat bladder strips. NAD-299 1 mumol kg(-1) i.v. suppressed oxyhaemoglobin-induced detrusor over-activity. It is concluded that NAD-299, acting at a supraspinal site, can inhibit micturition in the rat.