Prototypical antipsychotic drugs protect hippocampal neuronal cultures against cell death induced by growth medium deprivation

BACKGROUND: Several clinical studies suggested that antipsychotic-based medications could ameliorate cognitive functions impaired in certain schizophrenic patients. Accordingly, we investigated the effects of various dopaminergic receptor antagonists – including atypical antipsychotics that are prescribed for the treatment of schizophrenia – in a model of toxicity using cultured hippocampal neurons, the hippocampus being a region of particular relevance to cognition. RESULTS: Hippocampal cell death induced by deprivation of growth medium constituents was strongly blocked by drugs including antipsychotics (10(-10)-10(-6 )M) that display nM affinities for D(2 )and/or D(4 )receptors (clozapine, haloperidol, (±)-sulpiride, domperidone, clozapine, risperidone, chlorpromazine, (+)-butaclamol and L-741,742). These effects were shared by some caspases inhibitors and were not accompanied by inhibition of reactive oxygen species. In contrast, (-)-raclopride and remoxipride, two drugs that preferentially bind D(2 )over D(4 )receptors were ineffective, as well as the selective D(3 )receptor antagonist U 99194. Interestingly, (-)-raclopride (10(-6 )M) was able to block the neuroprotective effect of the atypical antipsychotic clozapine (10(-6 )M). CONCLUSION: Taken together, these data suggest that D2-like receptors, particularly the D(4 )subtype, mediate the neuroprotective effects of antipsychotic drugs possibly through a ROS-independent, caspase-dependent mechanism.