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 a ctivator (+/-)BAY k 8644 (2-trifluoromethylphenyl)-pyridine-5-carboxyl ate], the monoamine reuptake inhibitor cocaine and the monoamine relea ser d-amphetamine were determined alone and after pretreatment with th e structurally distinct L-type calcium channel blockers nimodipine (1, 4-dihydropyridine), verapamil (phenylakylamine), diltiazem (benzothiaz epine) and flunarizine (diphenylalkylamine) in squirrel monkeys respon ding under a 10-response fixed-ratio schedule of stimulus-shock termin ation. When administered alone, (+/-)BAY k 8644 (0.1-0.56 mg/kg) produ ced 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 lef tward and downward shift of the (+/-)BAY k 8644 dose-response curve. P retreatment with diltiazem (10-17.8 mg/kg) did not modify the (+/-)BAY k 8644 dose-effect curve. lh 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 adminis tered 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. Pretreatmen t with flunarizine (3.0 mg/kg) produced rightward shifts of the cocain e and d-amphetamine dose-response curves. Pretreatment with nimodipine (10 mg/kg), verapamil (3 mg/kg) or diltiazem (17.8 mg/kg) did not mod ify the effects of cocaine or d-amphetamine. The results of the presen t study suggest that the behavioral effects of (+/-)BAY k 8644 are dif ferentially modified by L-type calcium channel blockers interacting wi th different sites on the channel and also suggest that the calcium ch annel blockers can be distinguished based on their differing interacti ons with (+/-)BAY k 8644, cocaine and d-amphetamine.