Modification of the behavioral effects of (+/-)BAY k 8644, cocaine and d-amphetamine by L-type calcium channel blockers in squirrel monkeys.
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.
Rosenzweig-Lipson
S
S
Lederle Laboratories, American Cyanamid Company, Pearl River, NY, USA.
Barrett
J E
JE
D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology*; D000818:Animals; D001552:Benzazepines / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D003042:Cocaine / Q000494:pharmacology*; D003213:Conditioning, Psychological / Q000187:drug effects*; D003913:Dextroamphetamine / Q000494:pharmacology*; D004873:Ergolines / Q000494:pharmacology; D005444:Flunarizine / Q000494:pharmacology; D008297:Male; D019257:Quinpirole; D011954:Receptors, Dopamine / Q000502:physiology; D012453:Saimiri
D001552:Benzazepines; D002121:Calcium Channel Blockers; D004873:Ergolines; D011954:Receptors, Dopamine; D019257:Quinpirole; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; C067113:SK&F 81297; D003042:Cocaine; D005444:Flunarizine; D003913:Dextroamphetamine