Effects of dopamine D3 receptor antagonists on spontaneous and agonist-reduced motor activity in NMRI mice and Wistar rats: comparative study with nafadotride, U 99194A and SB 277011.

Abstract

Studies investigating the role of the dopamine D3 receptor in the regulation of motor activity of rodents have used several ligands; however, there have been few comparative studies using agonist-antagonist interactions. In the present study, we compared the effects of dopamine D3 antagonists with different levels of selectivity over D2 receptors (nafadotride, U 99194A and SB 277011) on motor activity as well as on agonist-induced hypoactivity, in mice and rats. Horizontal and vertical movements were measured in photocell activity cages. 7-Hydroxy-2-(di-n-propylamino)tetralin (7-OH-DPAT) and PD 128907 were used as dopaminergic agonists. Both dose-dependently inhibited motor activity in mice and vertical activity in rats, while decreasing horizontal activity of rats at doses of 0.01 and 0.1 mg/kg s.c., with no effect (7-OH-DPAT) or stimulation (PD 128907) at the 1 mg/kg dose. In mice habituated to the activity cage, nafadotride (0.1-3 mg/kg i.p.) caused a dose-dependent decrease in motor activity but did not affect the hypomotility evoked by either 7-OH-DPAT (0.1 mg/kg) or PD 128907 (0.1 mg/kg). In habituated rats it had no significant effect on motor activity and was not able to antagonize the hypoactivity caused by PD 128907 (0.1 mg/kg s.c.). U 99194A (5, 10 and 20 mg/kg s.c.) dose-dependently and significantly increased motor activity in mice and inhibited the effects of both agonists. In rats, nafadotride produced considerable motor stimulation and significantly inhibited the PD 128907-induced decrease in horizontal, but not in vertical, activity. SB 277011 (15-45 mg/kg p.o.) significantly increased motor activity in mice and partially blocked the action of 7-OH-DPAT on vertical, but not on horizontal, activity while against PD 128907, its significant inhibitory effect was restricted to a single dose (20 mg/kg). In habituated rats, SB 277011 (13.5, 20 and 30 mg/kg p.o.) exerted no significant effects on motor activity and did not antagonize the hypoactivity caused by PD 128907. Considerable species differences and movement-type differences (horizontal versus vertical) were observed between the effects of the tested dopamine D2/D3 ligands on motor activity in rodents. The antagonists also differed markedly in the robustness of their action. The poorly D3 selective antagonist, nafadotride, had little effect on motor behaviour. The moderately selective U 99194A exerted marked stimulatory effects on motility, and potently inhibited the actions of agonists. SB 277011, a highly selective dopamine D3 receptor antagonist, showed limited ability to influence the motor activity of rodents.