We have used the model of L-2-chloropropionic acid (L-CPA)-induced selective 
cerebellar granule necrosis to study excitatory amino acid-induced necrotic cell 
death in vivo produced by the activation of N-methyl-D-aspartate (NMDA) 
receptors. However, the mechanism for the NMDA receptor activation and the 
biochemical events which dictate the anatomical selectivity for the 
L-CPA-induced lesion are as yet unknown. We examined whether blockade of sodium 
and calcium channels may reduce the neurotoxicity through a reduction of 
glutamate release from granule cells. None of the sodium channel antagonists 
examined, i.e. phenytoin, lamotrigine or rilazole nor the mixed sodium/calcium 
channel blocker, lifarazine, altered the L-CPA neurotoxicity. However, L-type 
calcium channel blockers, verapamil and nifedipine enhanced the L-CPA-induced 
granule cell necrosis, assessed by measuring the degree of L-CPA-induced 
reductions in cerebellar aspartate concentration, increases in cerebellar 
glycine concentrations and the development of cerebellar oedema. In addition, 
the locomotor activity of rats receiving both L-CPA and either verapamil or 
nifedipine was significantly lower than when rats received L-CPA alone, 
suggesting an enhancement of the neurotoxicity of L-CPA by L-type calcium 
channel blockade. The data suggest that L-CPA may interfere with non-L-type 
calcium channels located on granule cell bodies and nerve terminals leading to 
reduction of the calcium entry into the cells. We suggest that a combination of 
L-type channel blockade and non-L-type channels which are sensitive to L-CPA 
produces reductions in intracellular calcium concentrations below that required 
for neuronal survival.