Dopaminergic mechanisms underlying bladder hyperactivity in rats with a unilateral 6-hydroxydopamine (6-OHDA) lesion of the nigrostriatal pathway

Abstract

1. This study was undertaken to elucidate dopaminergic mechanisms underlying bladder hyperactivity in a rat model of Parkinson's disease (PD) induced by a unilateral 6-OHDA injection into the substantia nigra pars compacta. 2. In 6-OHDA-lesioned rats, voided volume per micturition (0.41+/-0.04 ml, mean+/-s.e.m.) measured during 24 h in a metabolic cage was significantly smaller than in sham-operated rats (0.67+/-0.07 ml). 3. Cystrometrograms (CMG) in conscious animals revealed significantly smaller bladder capacity (BC) (0.46+/-0.03 ml) in 6-OHDA-lesioned rats than in sham rats (0.72+/-0.06 ml). 4. SKF38393 (D1/D5 receptor agonist, i.v.) significantly increased BC in 6-OHDA rats without apparent effects in sham rats. SKF38393 applied intracerebroventricularly (i.c.v.) under urethane anesthesia also increased BC in 6-OHDA-lesioned rats and by a smaller increment in sham rats. 5. In contrast, quinpirole (D2/D3/D4 receptor agonist, i.v.) significantly reduced BC in sham and 6-OHDA-lesioned rats. Intrathecal injection of quinpirole similarly reduced BC in sham and 6-OHDA-lesioned rats. 6. PD128907 (D(3)-receptor agonist) did not have significant effects on BC in 6-OHDA-lesioned rats. 7. These results indicate that a rat model of PD exhibited bladder hyperactivity as observed in patients with PD, and that stimulation of D1/D5 dopamine receptors at a supraspinal site can suppress bladder hyperactivity in PD, whereas stimulation of D2/D4, but not D3, dopamine receptors had the opposite effect to reduce bladder capacity. Thus, D1/D5 dopamine receptor agonists might be effective in treating neurogenic bladder hyperactivity in PD.

Figure 1

Photomicrographs of the substantia nigra showing cells with positive catecholamine fluorescence induced by the formaldehyde-induced fluorescence technique after 6-OHDA injection to the left side of substantia nigra (lesioned side). When compared with the intact side, there was a marked reduction of catecholamine-positive cells in the lesioned side where 6-OHDA was injected.

Figure 2

(a) Voided volume per micturition in a metabolic cage. Ordinate, voided volume (ml) per micturition. Note that 6-OHDA-treated rats (n=8) urinate with significantly smaller bladder capacity (0.41 ml) as compared with sham-operated rats (0.67 ml, n=6). ^**P<0.01 vs sham-operated rats. (b) Representative traces of cystometrogram in sham (top) and 6-OHDA-treated (bottom) rats. Recordings were obtained in awake animals. Ordinate, bladder pressure in cmH₂O. (c) Averaged bladder capacity inducing voiding. Ordinate, bladder volume (ml). Note that the bladder volume threshold in 6-OHDA-treated rats (0.46 ml, n=8) was significantly smaller than in sham-operated rats (0.63 ml, n=7). ^**P<0.01 vs sham-operated rats.

Figure 3

Effects of i.v. injection of SKF 38393 (1.0 mg kg⁻¹) on bladder activity in sham (a) and 6-OHDA-lesioned rats (b). Upper panels show cystometrograms during control periods, and lower panels show the recordings 5 min after the drug application. Note that SKF 38393 increased intercontraction intervals in 6-OHDA-lesioned rats, but not in sham-operated rats.

Figure 4

Effects of i.c.v. application of SKF 38393 (5.0 μg) on bladder activity in sham (a) and 6-OHDA-lesioned rats (b). Arrows indicate the time of drug administration. Note that SKF 38393 increased intercontraction intervals in both the groups of animals, and the effect was much greater in 6-OHDA-lesioned rats.

Figure 5

Effects of i.t. injection of SKF 38393 (5.0 μg) on bladder activity in sham (a) and 6-OHDA-lesioned rats (b). Arrows indicate the time of drug administration. Note that SKF 38393 did not induce significant changes in intercontraction intervals in either sham or 6-OHDA-lesioned rats.

Figure 6

Effects of i.v. application of quinpirole (0.4 mg kg⁻¹) on bladder activity in sham (a) and 6-OHDA-lesioned rats (b). Arrows indicate the time of drug administration. Note that quinpirole reduced intercontraction intervals in both sham and 6-OHDA-lesioned rats.

Figure 7

Effects of i.c.v. application of quinpirole (2.0 μg) on bladder activity in sham (a) and 6-OHDA-lesioned rats (b). Arrows indicate the time of drug administration. Note that quinpirole reduced intercontraction intervals in both sham and 6-OHDA-lesioned rats, but to a smaller degree than the effects seen after i.v. injection of quinpirole (Figure 6).

Figure 8

Effects of i.t. application of quinpirole (2.0 μg) on bladder activity in sham (a) and 6-OHDA-lesioned rats (b). Arrows indicate the time of drug administration. Note that quinpirole reduced intercontraction intervals in both sham and 6-OHDA-lesioned rats in a similar manner as observed after i.v. injection of quinpirole (Figure 6).

Figure 9

Effects of i.v. and i.t. application of PD128907 (0.25 mg kg⁻¹ and 1.5 μg, respectively) on bladder activity in sham (a) and 6-OHDA-lesioned rats (b). Arrows indicate the time of drug administration. Note that PD128907 did not induce significant changes of intercontraction intervals in either sham or 6-OHDA-lesioned rats.