FLUSPIRILENE BLOCK OF N-TYPE CALCIUM CURRENT IN NGF-DIFFERENTIATED PC12 CELLS

1 High voltage-activated calcium currents were recorded in nerve growt h factor (NGF)-differentiated PC12 cells with the whole-cell patch cla mp technique. After exposure to NGF for 3-10 days the PC12 cells devel oped neurone-like processes and calcium currents which were pharmacolo gically separable into L- and N-types (defined by sensitivity to nifed ipine and omega-conotoxin GVIA respectively). 2 After blocking the L-t ype calcium channels with nifedipine (1O mu M), omega-conotoxin GVIA b locked approximately 85% of the remaining calcium current with an IC50 of 3nM and a Hill coefficient of 1. The block by conotoxin GVIA was i rreversible on the time scale of these experiments. These results sugg ested that the majority of the nifedipine-insensitive calcium current was N-type. 3 Fluspirilene, a substituted diphenylbutylpiperidine with potent neuroleptic properties, reversibly inhibited the N-type compon ent in a dose-dependent manner with an IC50 of 30nM. The Hill coeffici ent of the block was 0.25. The fraction of current blocked was the sam e at all test potentials examined (-30 to +40mV). 4 These data indicat e that the neuroleptic properties of fluspirilene may be due, at least in part, to an inhibition of neuronal N-type calcium channels. This f inding raises the possibility that modulation of N-type calcium channe l activity by drugs derived from substituted diphenylbutylpiperidines may provide a novel way of altering neurotransmitter release and hence brain function.