EFFECTS OF DIHYDROPYRIDINE CA2+ CHANNEL BLOCKERS ON THE DISCRIMINATIVE STIMULUS AND THE MOTOR IMPAIRING EFFECTS OF (+ -)-BAY K-8644/

Functional interactions between the dihydropyridine Ca2+ channel activ ator, (+/-)-Bay K 8644 -(2-trifluoromethyphenyl)-pyridine-5-carboxylat e), and several dihydropyridine L-type Ca2+ channel blockers were inve stigated on rotarod performance in mice and in rats trained to discrim inate between (+/-)Bay K 8644 and saline. When administered alone, (+/ -)-Bay K 8644 produced dose-dependent impairments of rotarod activity with an ED50 of 1.3 mg/kg. Pretreatment with nifedipine (10-30 mg/kg) produced dose-dependent rightward shifts of the (+/-)-Bay K 8644 dose- response curve. In contrast, pretreatment with several other dihydropy ridine L-type Ca2+ channel blockers, including nicardipine, nimodipine , isradipine and nitrendipine, did not modify the (+/-)-Bay K 8644 dos e-effect function. Rats learned to discriminate between (+/-)-Bay K 86 44 (0.5 mg/kg) and saline in an average of 65 training sessions. In su bstitution tests, the Ca2+ channel activator engendered dose-related i ncreases in the percentage of rats selecting the drug-associated lever with an ED50 of 0.19 mg/kg. Pretreatment with nifedipine (10 mg/kg) p roduced a rightward shift of the (+/-)-Bay K 8644 dose-response functi on. Pretreatment with nicardipine (2.5 mg/kg) only partially antagonis ed the training dose of (+/-)-Bay K 8644 whereas nimodipine (0.6-10 mg /kg) did not affect the (+/-)-Bay K 8644 discriminative stimulus. The results of the present study show that the behavioural effects of the dihydropyridine Ca2+ channel activator are differentially modified by dihydropyridine L-type Ca2+ channel blockers. These results may sugges t that dihydropyridine blockers possess different intrinsic activities or act at different binding sites. (C) 1997 Elsevier Science B.V.