CHOLECYSTOKININ-B RECEPTOR ANTAGONISTS ENHANCE THE LOCOMOTOR RESPONSETO THE N-METHYL-D-ASPARTATE ANTAGONISTS PHENCYCLIDINE AND DIZOCILPINEMALEATE

The cholecystokinin antagonists L-740;093, L-365,260, LY-288513 and CI 988, which are all selective for the cholecystokinin(B) receptor subty pe, were examined for their ability to modulate locomotor activity ind uced 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 b y subcutaneous administration of phencyclidine (2 mg/kg) were signific antly potentiated by intraperitoneal (i.p.) administration of L-740,09 3 (1 mg/kg), L-365,260 (10 mg/kg), LY-288513 (10 mg/kg), but, not CI-9 88 (10 mg/kg). Locomotor activity induced by subcutaneous administrati on 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 admi nistered alone did not alter spontaneous locomotor activity (motility) as compared to vehicle/saline controls. However, when these antagonis ts were administered to naive, unhabituated rats, L-365,260 and LY-288 513 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 enviro nment (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 effe ct on locomotion elicited by phencyclidine and MK-801, and that this i nhibitory action of cholecystokinin is mediated via the cholecystokini n, receptor, since it can be eliminated by administration of cholecyst okinin, antagonists. It is suggested that the site of action of the ch olecystokinin, receptors involves mainly the cholecystokinin/glutamate projection from the cortex to the anterior nucleus accumbens and/or s triatum. Finally, the present study provides two examples of endogenou s release of a neuropeptide resulting in behavioural consequences. Cop yright (C) 1996 IBRO. Published by Elsevier Science Ltd.