Despite the existence of some positive and negative reports on dantrolene in ischemic states, combined application of an endoplasmic reticulum Ca2+ release inhibitor and a calcium channel blocker has not yet been elucidated. In the present study, we have investigated the role of dantrolene in subsequent doses alone or in coexistence with the dihydropyridine calcium antagonist nimodipine (10(-4) M concentration) in glutamate-induced (10(-7) M) neurotoxicity in cerebellar granular cell cultures of rat pups, Glutamate induced neuronal cell death at a concentration of 10(-7) M. Despite the fact that none of the groups tested were able to reverse cell death to control values, dantrolene was found to be effective in preventing glutamate toxicity in cerebellar cultures of rat pups. The protective effect of dantrolene potentialized in combination with nimodipine at all doses tested. The most effective dose of dantrolene was found to be 10(-4) M in combination with nimodipine. As a result, both extracellular and internal calcium stores play important roles in the genesis of neuronal cell death induced by glutamate. (C) 2001 Academic Press.