Elsevier

Brain Research

Volume 946, Issue 2, 16 August 2002, Pages 290-297
Brain Research

Research report
The role of 5-HT1A receptors in control of lower urinary tract function in cats

https://doi.org/10.1016/S0006-8993(02)02897-4Get rights and content

Abstract

In the present study, the role of 5-HT1A receptors in control of lower urinary tract function in cats was examined using 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) and 5-methoxy-N,N-dimethyltryptamine (5-MeODMT) as agonists and WAY100635 and LY206130 as antagonists. Bladder function was assessed using cystometric infusion of saline or 0.5% acetic acid to produce bladder irritation. External urethral sphincter (EUS) function was assessed using electromyographic (EMG) recordings of activity recorded during cystometry or by recording electrically evoked pudendal reflexes. Both 5-HT1A receptor agonists caused dose-dependent decreases in bladder activity and increases in EUS EMG activity under conditions of acetic acid infusion. 5-HT1A receptor antagonists reversed both the bladder-inhibitory and sphincter-facilitatory effects. Thus, 5-HT1A receptor activation can have opposite effects on nociceptive afferent processing depending upon the efferent response being measured. During saline infusion of the bladder, 8-OH-DPAT produced moderate inhibition of bladder activity and had no significant effect on sphincter electromyographic (EMG) activity. 8-OH-DPAT either had no effect, or inhibited, low-threshold electrically evoked pudendal reflexes. These findings indicate that 5-HT1A receptor stimulation is inhibitory to bladder function in cats, especially under conditions where the bladder is hyperactive due to irritation. Furthermore, these bladder-inhibitory effects are the exact opposite of the bladder-excitatory effects of 8-OH-DPAT reported in rats. 5-HT1A receptor stimulation increases EUS motoneuron activity when driven by nociceptive bladder afferent inputs but not when driven by non-nociceptive afferent inputs. In summary, 5-HT1A receptor agonists facilitate a nociceptor-driven spinal reflex (sphincter activity) but inhibit a nociceptor-driven supraspinal reflex (micturition). This pattern of activity would facilitate urine storage and may be important under ‘fight-or-flight’ conditions when serotonergic activity is high.

Introduction

Various studies have implicated serotonin (5-hydroxytryptamine, 5-HT) in control of lower urinary tract function. 5-HT terminals and various receptor subtypes are intimately associated with spinal cord areas that contain afferent and efferent components of lower urinary tract neural control centers [3], [15], [18], [27], [37]. Pharmacological and physiological studies have indicated that the serotonergic system influences neural control of lower urinary tract function [6], [11], [13], [19], [21], [30], [32], [36].

One receptor subtype that appears to be particularly localized to spinal cord regions that subserve lower urinary tract function is the 5-HT1A receptor subtype [37]. In both rat and cat, this receptor subtype shows moderate to dense binding in areas of the dorsal horn that contain bladder afferent terminals [24], [26], in the sacral parasympathetic nucleus, which contains efferent innervation of the bladder [23], [26], and in rat and cat homologs of Onuf’s nucleus, which contain urethral sphincter motor neurons [20], [35].

Pharmacological studies of 5-HT1A receptor activation in rats showed that 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), the prototypical 5-HT1A receptor agonist [16], [22], produced a micturition contraction when bladder volume was just subthreshold for producing a physiological bladder contraction [19]. This implied that 5-HT1A receptor activation facilitates bladder activity in the rat. However, in cats [36], 5-methoxy-N,N-dimethyltryptamine (5-MeODMT), a non-selective 5-HT1A receptor agonist, inhibited bladder activity.

Thus, the current study was undertaken to more precisely define the role of 5-HT1A receptors in regulation of bladder function in the cat and to determine its effects on external urethral sphincter activity using more selective 5-HT1A receptor agonists and antagonists. Additionally, the effects of the drugs were examined under conditions of bladder irritation.

Section snippets

Methods

Transvesical cystometrograms (CMG) were performed as previously described in detail [32]. Briefly, 19 adult female cats were anesthetized with α-chloralose (50–75 mg/kg i.v., Sigma, St. Louis, MO, USA). Following a midline laparotomy, the bladder was cannulated through the dome to allow infusion of fluids and recording of intravesical pressure. The urethra remained patent to allow expulsion of fluids during reflex micturition. In five animals, CMGs were recorded by emptying the bladder,

Results

Under control conditions (Fig. 1A), large (30–50 cm H2O), rapid increases in intravesical pressure (i.e. micturition contractions) were recorded after infusion of approximately 5 ml saline into an initially empty bladder. Upon switching to infusion of acetic acid (Fig. 1B), bladder capacity, contraction amplitude, and contraction duration were reduced, while the contraction frequency was increased as previously reported [32]. Very little peri-urethral EMG activity was recorded during infusion

Discussion

The present study has shown that 5-HT1A receptor activation inhibits bladder activity (i.e. decrease in contraction frequency and increase in capacity) and facilitates EUS EMG activity under conditions of acetic acid infusion into the bladder. 8-OH-DPAT is a fairly selective 5-HT1A receptor agonist, while 5-MeODMT is less selective [16], [22]. However, since the effects of both agonists were blocked by two selective 5-HT1A receptor antagonists [12], [16], the results strongly suggest that the

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