EFFECTS OF CALCIUM-ANTAGONISTS ON THE DOPAMINE SYSTEM

Calcium channel antagonists are drugs currently used in the treatment of neurological and cardiovascular disorders and occasionally produce parkinsonism and movement disorders as a side effect. We investigated the effects of calcium channel antagonists on the pharmacology of dopamine systems in vivo and in vitro. Flunarizine, cinnarizine, and diltiazem reduce the viability of dopamine-rich human neuroblastoma cells in vitro. These compounds plus verapamil, nifedipine, and nicardipine reduce H-3-spiperone binding to bovine striatal membranes, H-3-dopamine uptake, K+-induced H-3-dopamine release, and apomorphine-induced rotation, but not amphetamine-induced rotation, in 6-OH-dopamine-lesioned rats. Therefore, all calcium channel antagonists tested reduce dopamine neurotransmission in vitro and in vivo, whereas the evidence of toxicity for dopamine cells in vitro is restricted to flunarizine, cinnarizine, and diltiazem. The clinical relevance of these toxic effects may depend on several factors, including age, penetration across the blood-brain barrier, and types of calcium channels present in the different neuronal subtypes. On the other hand, the finding of dopamine-regulating properties not associated to neurotoxic effects in the dihydropyridines and verapamil provides new putative therapeutic tools for the treatment of neurologic disorders associated with dopamine hyperactivity.