Inhibition of [3H]dopamine uptake by flunarizine.
The effect of different calcium channel blockers was studied on basal and cocaine-inhibited [3H]dopamine uptake in rat striatal synaptosomes. Isradipine (dihydropyridine calcium antagonist) and diltiazem (L-type calcium antagonist) were devoid of effect on [3H]dopamine uptake, while flunarizine (T-type calcium antagonist) inhibited [3H]dopamine uptake. Flunarizine inhibition was competitive and the inhibitory curve was biphasic with a Hill coefficient of 2.1. The high Hill number suggested a mechanism of positive cooperativity between two sites. Flunarizine inhibition showed a complex interaction with cocaine inhibition. While flunarizine at low concentrations interacts with a distinct site, at higher concentrations it interacts with the same site as cocaine. The relevance of this finding for the potentiation by flunarizine of cocaine-induced dopamine release in vivo is discussed.
Devoto
P
P
Institute of Pharmacology and Biochemical Pathology, Cagliari, Italy.
Pani
L
L
Kuzmin
A
A
De Montis
G
G
D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology; D003042:Cocaine / Q000494:pharmacology; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D003864:Depression, Chemical; D004298:Dopamine / Q000378:metabolism*; D005444:Flunarizine / Q000494:pharmacology*; D066298:In Vitro Techniques; D007700:Kinetics; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism
D002121:Calcium Channel Blockers; D003042:Cocaine; D005444:Flunarizine; D004298:Dopamine