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S Rosenzweig-Lipson and JE Barrett
Lederle Laboratories, American Cyanamid Company, Pearl River, NY, USA.
Behavioral effects of the 1,4-dihydropyridine L-type calcium channel activator (+/-)BAY k 8644 [(+/-)methyl-1,4-dihydro-2,6-dimethyl-3- nitro-4-(2-trifluoromethylphenyl)-pyridine-5-carboxylate] the monoamine reuptake inhibitor cocaine and the monoamine releaser d-amphetamine were determined alone and after pretreatment with the structurally distinct L-type calcium channel blockers nimodipine (1,4- dihydropyridine), verapamil (phenylakylamine), diltiazem (benzothiazepine) and flunarizine (diphenylalkylamine) in squirrel monkeys responding under a 10-response fixed-ratio schedule of stimulus- shock termination. When administered alone, (+/-)BAY k 8644 (0.1-0.56 mg/kg) produced dose-dependent decreases in rates of responding. Pretreatment with nimodipine (3.0-10 mg/kg) or verapamil (1.0-3.0 mg/kg) produced dose-dependent rightward shifts of the (+/-)BAY k 8644 dose-response curve. In contrast, pretreatment with flunarizine (3.0 mg/kg) produced a leftward and downward shift of the (+/-)BAY k 8644 dose-response curve. Pretreatment with diltiazem (10-17.8 mg/kg) did not modify the (+/-)BAY k 8644 dose-effect curve. In addition, stereoselectivity was evident in the behavioral effects of (+/-)BAY k 8644 with the S(-)-enantiomer being approximately 3-fold more potent than the racemate. When administered alone, cocaine (0.1-5.6 mg/kg) and d-amphetamine (0.1-3.0 mg/kg) produced dose-dependent decreases in rates of responding. Pretreatment with flunarizine (3.0 mg/kg) produced rightward shifts of the cocaine and d-amphetamine dose-response curves. Pretreatment with nimodipine (10 mg/kg), verapamil (3 mg/kg) or diltiazem (17.8 mg/kg) did not modify the effects of cocaine or d- amphetamine. The results of the present study suggest that the behavioral effects of (+/-)BAY k 8644 are differentially modified by L- type calcium channel blockers interacting with different sites on the channel and also suggest that the calcium channel blockers can be distinguished based on their differing interactions with (+/-)BAY k 8644, cocaine and d-amphetamine.
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