Cholecystokinin B receptor antagonists enhance the locomotor response to the N-methyl-D-aspartate antagonists phencyclidine and dizocilpine maleate.

ABSTRACT

The cholecystokinin antagonists L-740,093, L-365,260, LY-288513 and CI988, which are all selective for the cholecystokininB receptor subtype, were examined for their ability to modulate locomotor activity induced by the non-competitive N-methyl-D-aspartate receptor antagonists phencyclidine and dizocilpine maleate (MK-801) in habituated rats. It was found that the locomotor effects (motility, locomotion) produced by subcutaneous administration of phencyclidine (2 mg/kg) were significantly potentiated by intraperitoneal (i.p.) administration of L-740,093 (1 mg/kg), L-365,260 (10 mg/kg), LY-288513 (10 mg/kg), but not CI-988 (10 mg/kg). Locomotor activity induced by subcutaneous administration of MK-801 (0.15 mg/kg) was potentiated by intraperitoneal L-740,093 (0.3, 1 and 3 mg/kg). L-740,093, L-365,260, LY-288513 and CI-988 administered alone did not alter spontaneous locomotor activity (motility) as compared to vehicle/saline controls. However, when these antagonists were administered to naive, unhabituated rats, L-365,260 and LY-288513 caused a significant reduction in motility compared to the vehicle control. These findings suggest that, although cholecystokinin may be involved in exploratory behaviour exhibited by rats in a novel environment (unhabituated rats), its role is negligible in rats subjected to a familiar environment (habituated rats). Furthermore, these results support the interpretation that cholecystokinin has a suppressant effect on locomotion elicited by phencyclidine and MK-801, and that this inhibitory action of cholecystokinin is mediated via the cholecystokininB receptor, since it can be eliminated by administration of cholecystokininB antagonists. It is suggested that the site of action of the cholecystokininB receptors involves mainly the cholecystokinin/glutamate projection from the cortex to the anterior nucleus accumbens and/or striatum. Finally, the present study provides two examples of endogenous release of a neuropeptide resulting in behavioural consequences.