Local Change in Urinary Bladder Contractility Following CNS Dopamine Denervation in the 6-OHDA Rat Model of Parkinson’s Disease

Abstract

Background: Urinary problems, including urinary frequency, urgency, and nocturia are some of the non-motor symptoms that correlate most with poor quality of life in Parkinson’s disease. However, the mechanism behind these symptoms is poorly understood, in particular regarding peripheral bladder pathophysiology following dopamine degeneration.Objective: In this study, we compared the contractile responsiveness of urinary bladder from the 6-OHDA unilateral rat model of Parkinson’s disease with that of normal untreated animals.Methods: The contractility of the urinary detrusor muscle was evaluated in bladder strip preparations using electrical field stimulation, and muscarinic and purinoceptor stimulations in an vitro organ bath setup.Results: Our data show that the overall contractile response following electrical field stimulation was significantly higher (43% at maximum contraction by 20–40 Hz stimulation) in the 6-OHDA-lesioned rats as compared to control animals. This increase was associated with a significant increase in the cholinergic contractile response, where the muscarinic agonist methacholine produced a 44% (at 10 −4 M concentration) higher response in the 6-OHDA-treated rats as compared to controls with a significant left-shift of the dose response. This indicates an altered sensitivity of the muscarinic receptor system following the specific central 6-OHDA-induced dopamine depletion. In addition a 36% larger contraction of strips from the 6-OHDA animals was also observed with purinoceptor activation using the agonist ATP (5×10 −3 M) during atropine treatment.Conclusions: Our data shows that it is not only the central dopamine control of the micturition reflex that is altered in Parkinson’s disease, but also the local contractile function of the urinary bladder. The current study draws attention to a mechanism of urinary dysfunction in Parkinson’s disease that has previously not been described.

Altered detrusor contractility in MPTP-treated common marmosets with bladder hyperreflexia

“…This suggests that there is no local dopaminergic contribution to detrusor activity in contrast to the centrally mediated effects on hyperreflexia observed in the whole animal. However, in contrast to the present finding, it was shown recently that following lesioning of the nigrostriatal tract with 6-hydroxydopamine, rat detrusor strips produced greater contraction to both methacholine and ATP [ 26 ]. The apparent difference between our data in common marmosets and those in the rat [ 26 ] require further investigation but may be related to differences in the species or the differences in experimental paradigms.…”

“…However, in contrast to the present finding, it was shown recently that following lesioning of the nigrostriatal tract with 6-hydroxydopamine, rat detrusor strips produced greater contraction to both methacholine and ATP [ 26 ]. The apparent difference between our data in common marmosets and those in the rat [ 26 ] require further investigation but may be related to differences in the species or the differences in experimental paradigms. The observed differences cannot be attributed to muscle hypertrophy as care was taken to prepare strips of similar size and proportions and the agonist induced contractile responses were not different in the same tissues that responded differently to EFS.…”

“…Although we did not quantify changes in the morphology of the bladder, but changes in the appearance of the bladder has been reported in various models of PD elsewhere [26, 27]. In the current experiments where MPTP treatment resulted in >80% loss of dopaminergic neurones in the substantia nigra, loss of nigrostriatal dopaminergic innervation appears to lead to long-term changes in bladder anatomy and neural physiology.…”

“…We have previously reported the occurrence of bladder hyperreflexia in MPTP-treated primates associated with increased micturition frequency [ 6 ] and in this study, one of the first observations following necropsy was the increased size of bladders in MPTP-treated animals. Although we did not quantify changes in the morphology of the bladder, but changes in the appearance of the bladder has been reported in various models of PD elsewhere [ 26 , 27 ]. In the current experiments where MPTP treatment resulted in >80% loss of dopaminergic neurones in the substantia nigra, loss of nigrostriatal dopaminergic innervation appears to lead to long-term changes in bladder anatomy and neural physiology.…”

Animal Model for Lower Urinary Tract Dysfunction in Parkinson’s Disease

“…It has been suggested that not only is there an alteration of the central dopamine control of the micturition reflex in PD, but also there is a local contractile function of the urinary bladder [ 28 ]. Mitra et al reported finding there was an altered contractile function caused by local morphological changes and plasticity in the urinary bladder in a rat PD model.…”