Fig. 5.

Non-catechol agonists elicit sustained responses after repeated dosing in vivo. Eye blink rates (EBR) in cynomolgus monkeys (n = 3) were assessed as a measure of central D1R activation over 6 h after administration of vehicle and repeated administration of agonists daily for 3 days. Dosing of agonists was chosen to give matched D1R occupancy. a Monkey eye blink rates over a 6 h period after vehicle or subcutaneous dosing of A-77636 (1 mg/kg). EBR was significantly greater than vehicle group at days 1 (***P = 0.0003) and 2 (*P = 0.0024), but not different for day 3 (P = 0.065); EBR on day 3 was significantly lower than on day 1 (^#P = 0.011). b EBR over 6 h after vehicle or oral administration of PF-2334 (0.6 mg/kg + 0.3 mg/kg 8 h later). EBR was significantly greater than vehicle values for day 1 (**P = 0.010), day 2 (**P = 0.0038), and day 3 (*P = 0.035). EBR on days 1,2,3 showed no pairwise difference. c Eye blink rates over the 6 h period after drug administration were combined and are expressed as percent of day one response, n = 3 per group. d Contralateral rotations in rats with confirmed unilateral 6-OHDA lesions after administration of D1R agonists every 12 h. Rotations per minute were measured for the 6 h immediately following subcutaneous doses of A-77636 (0.32 mg/kg, red bars) or oral doses of PF-2334 (10.78 mg/kg, green bars). Two-way ANOVA revealed significant effect of treatment (P = 0.022) and time (P < 0.0001) but not interaction (P = 0.068). After 36 h, PF-2334 treated animals had significantly greater rotational behavior than A-77636 treated animals (*P < 0.05). All data are presented as means ± s.e.m. For full time-course of rotational behavior see Supplementary Fig. 5