EFFECTS OF ISRADIPINE AND DARODIPINE ON SEROTONERGIC SYSTEM OF THE RAT-BRAIN

Isradipine and darodipine are dihydropyridine calcium antagonists that easily pass into the brain, showing high affinity for cerebral L-type voltage-sensitive calcium channel (VSCC). These drugs were IP adminis trered to rats to study their effects on serotonergic systems of discr ete brain areas. Isradipine (0.05-5.0 mg/kg) and darodipine (0.3-20 mg /kg) increased the 5-HIAA/5-HT ratio, mostly enhancing the metabolite (5-HIAA) content in various brain areas, suggesting that serotonin (5- HT) turnover was increased. This increase appeared to depend on facili tation of serotonergic neurotransmission, because low doses of isradip ine (< 0.075 mg/kg) or darodipine (<0.6 mg/kg) enhanced the number of head twitches induced by L-5-hydroxytryptophan (L-5-HTP). However, hig her doses of isradipine (1.5 mg/kg) or darodipine (5 mg/kg) also appea red to stimulate a negative feedback mechanism, which predominated ove r the facilitation when the serotonergic neurotransmission was strongl y activated. Thus, higher drug doses decreased both the serotonin turn over and the number of head twitches on rats treated with L-5-HTP. It was speculated that the observed effects were due to brain VSCC blocka de, although the studied compounds showed a peculiar profile of proper ties when compared to other previously studied calcium antagonists. Mo reover, it was concluded that darodipine appeared to be mole effective and selective than isradipine regarding the effects on brain serotone rgic systems.