Haloperidol and atypical antipsychotics share a same action of decreasing P75NTR mRNA levels in PC12 cells

P75NTR is a common neurotrophin receptor which binds all neurotrophins with similar affinities and has been shown to be capable of mediating programmed cell death. In this study, we investigated effects of the antipsychotic drugs (APDs) haloperidol, clozapine, quetiapine, and risperidone on p75NTR mRNA levels in PC12 cells. Haloperidol is a prototype of typical APDs, and the other three drugs are atypical APDs, which are effective in reducing negative symptoms and cognitive deficits of schizophrenia, cause less side effects, and are more tolerable compared to haloperidol. PC12 cells were cultured with various concentrations of haloperidol, clozapine, quetiapine, or risperidone, in their media. After culture for 48 h, the cell viabilities and p75NTR mRNA levels were measured. It was shown that both haloperidol and the atypical APDs used in this study deceased p75NTR mRNA levels in PC12 cells in a dose dependent manner, while not affecting cell viabilities. In further experiments, doses that produced significant/greatest effects were chosen and provided in the culture media for various periods. Decreases in p75NTR mRNA levels were observed in cultures treated for 12 h with quetiapine, 24 h with clozapine or risperidone, or for 48 h with haloperidol. These results suggest that both haloperidol and atypical APDs have the same action of decreasing p75NTR mRNA levels in PC12 cells. Although the underlying molecular mechanism of this action remains to be elucidated, this finding is particularly relevant given the neurodevelopmental deficits associated with schizophrenia and important roles of p75NTR in mediating cell death.