BAM-1110

The effects of dopamine receptor agonists on urinary bladder function were evaluated in normal and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned parkinsonian cynomolgus monkeys to investigate the therapeutic efficacy in the treatment of urinary symptoms in Parkinson's disease. Under ketamine anesthesia, cystometrograms exhibited significant reduction in the volume threshold for the micturition reflex in MPTP-lesioned parkinsonian monkeys when compared with those of normal monkeys. The selective dopamine D2 receptor agonist bromocriptine significantly reduced the bladder volume threshold for the micturition reflex by 25 to 30% in both normal and MPTP-lesioned animals. The nonselective D1/D2 receptor agonist pergolide significantly reduced the bladder volume threshold by 22% in normal monkeys, but increased the volume threshold by 50% in MPTP-lesioned parkinsonian monkeys. Another D1/D2 agonist (5R,8R,10R)-6-methyl-8-(1,2,4-triazol-1-ylmethyl) ergoline maleate (BAM-1110) also increased the bladder volume threshold (by 80%) in parkinsonian monkeys without significant effects on the micturition reflex in normal monkeys. The reduction in the volume threshold by bromocriptine in both normal and MPTP-treated groups and by pergolide in normal monkeys was suppressed by pretreatment with the selective D2 antagonist sulpiride, whereas the increment in the volume threshold by pergolide and BAM-1110 in parkinsonian monkeys was antagonized by pretreatment with the selective D1 antagonist SCH 23390, but not by sulpiride. These findings suggest that concurrent activation of D1/D2 receptors, rather than selective stimulation of D2 receptors, might be beneficial for treating urinary symptoms caused by detrusor hyperreflexia in Parkinson's disease.