The influence of duloxetine on detrusor overactivity in rats with depression induced by 13-cis-retinoic acid

Abstract

Introduction and hypothesis: The aim of this study was to assess the efficacy of duloxetine in an animal model of detrusor overactivity induced by depression.

Methods: After 6 weeks of 13-cis-retinoic acid administration at a dose of 1 mg/kg/day, rats were given duloxetine at a dose of 1 mg/kg. This was followed by conscious cystometry, a forced swim test, and locomotor activity measurement. The levels of corticotropin-releasing factor (CRF) in the hypothalamus, amygdala and plasma were also determined.

Results: Duloxetine treatment led to a reduction in detrusor overactivity symptoms induced by the retinoid. Decreases were observed in cystometric parameters including the detrusor overactivity index, and the amplitude and frequency of nonvoiding contractions, while increases were seen in bladder compliance and the volume threshold to elicit nonvoiding contractions. No statistically significant differences were found in basal pressure, threshold pressure, micturition voiding pressure, postvoid residual , volume threshold, voiding efficiency, intercontraction interval, bladder contraction duration or relaxation time. Duloxetine also reduced the immobility time to that observed in control animals, while it did not affect locomotor activity. Its effects also included lowering of the CRF levels in the hypothalamus, amygdala and plasma, which increased following the prior administration of the retinoid. The plasma level of 13-cis-retinoic acid in rats corresponded to the levels found in humans.

Conclusions: This is the first study showing the efficacy of duloxetine in an animal model of detrusor overactivity induced by depression. Further studies in patients with detrusor overactivity and coexisting depression are warranted to confirm these experimental results.

Keywords: Cystometry; Depression; Detrusor overactivity; Duloxetine; Rats.

Fig. 1

Mean values of cystometric parameters (basal pressure, threshold pressure, micturition voiding pressure, voided volume, postvoid residual, and volume threshold) characteristic of detrusor overactivity induced by treatment with 13-cis-RA in the different treatment groups showing the effects of treatment with duloxetine (CON control group). a Basal pressure (***p < 0.001, CON vs. 13-cis-RA). b Threshold pressure (***p < 0.001, CON vs. 13-cis-RA). c Micturition voiding pressure (**p < 0.01, CON vs. 13-cis-RA). d Voided volume (*p < 0.05, CON vs. 13-cis-RA). e Postvoid residual. f Volume threshold (**p < 0.01, CON vs. 13-cis-RA). All results are presented as means ± SEM (n = 15 rats per group). The data obtained were evaluated using one-way analysis of variance followed by Tukey’s post hoc test. *p < 0.05, **p < 0.01, ***p < 0.001

Fig. 2

Mean values of cystometric parameters (voiding efficiency, intercontraction interval, bladder contraction duration, relaxation time, bladder compliance, and detrusor overactivity index) characteristic of detrusor overactivity induced by treatment with 13-cis-RA in the different treatment groups showing the effects of treatment with duloxetine (CON control group). a Voiding efficiency. b Intercontraction interval (***p < 0.001, CON vs. 13-cis-RA). c Bladder contraction duration. d Relaxation time. e Bladder compliance (***p < 0.001, CON vs. 13-cis-RA; ^^p < 0.01, 13-cis-RA vs. 13-cis-RA + duloxetine. f Detrusor overactivity index (***p < 0.001, CON vs. 13-cis-RA; ^^^p < 0.001, 13-cis-RA vs. 13-cis-RA + duloxetine). All results are presented as means ± SEM (n = 15 rats per group). The data obtained were evaluated using one-way analysis of variance followed by Tukey’s post hoc test. ^^p < 0.01, ^^^p < 0.001, ***p < 0.001

Fig. 3

Mean values of cystometric parameters (amplitude of nonvoiding contractions, frequency of nonvoiding contractions, and volume threshold to elicit nonvoiding contractions) characteristic of detrusor overactivity induced by treatment with 13-cis-RA in the different treatment groups showing the effects of treatment with duloxetine (CON control group). a Amplitude of nonvoiding contractions (***p < 0.001, CON vs. 13-cis-RA; ^^^p < 0.001, 13-cis-RA vs. 13-cis-RA + duloxetine). b Frequency of nonvoiding contractions (***p < 0.001, CON vs. 13-cis-RA; ^^^p < 0.001, 13-cis-RA vs. 13-cis-RA + duloxetine). c Volume threshold to elicit nonvoiding contractions (***p < 0.001, CON vs. 13-cis-RA; ^p < 0.05, 13-cis-RA vs. 13-cis-RA + duloxetine). All results are presented as means ± SEM (n = 15 rats per group). The data obtained were evaluated using one-way analysis of variance followed by Tukey’s post hoc test. ^p < 0.05, ^^^p < 0.001, ***p < 0.001

Fig. 4

Immobility times in rats in the different treatment groups. All results are presented as means ± SEM (n = 15 rats per group). The data obtained were evaluated using one-way analysis of variance (ANOVA) followed by Tukey’s post hoc test

Fig. 5

locomotor activity (number of movements) in rats in the different treatment groups. All results are presented as the means ± SEM (n = 15 rats per group). The data obtained were evaluated using one-way analysis of variance followed by Tukey’s post hoc test

Fig. 6

Mean CRF levels in the hypothalamus, amygdala and plasma of rats in the different treatment groups (CON control group). a Hypothalamus (***p < 0.001, CON vs. 13-cis-RA; ^^^p < 0.001, 13-cis-RA vs. 13-cis-RA + duloxetine). b Amygdala (***p < 0.001, CON vs. 13-cis-RA; ^^^p < 0.001, 13-cis-RA vs. 13-cis-RA + duloxetine). c Plasma (***p < 0.001, CON vs. 13-cis-RA; ^^^p < 0.001, 13-cis-RA vs. 13-cis-RA + duloxetine). All results are presented as means ± SEM (n = 15 rats per group). The data obtained were evaluated using one-way analysis of variance followed by Tukey’s post hoc test. ^^^p < 0.001, ***p < 0.001