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.