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<p>Abstract</p> <p>Background</p> <p>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.</p> <p>Results</p> <p>Hippocampal cell death induced by deprivation of growth medium constituents was strongly blocked by drugs including antipsychotics (10^-10-10^-6M) that display nM affinities for D₂and/or D₄receptors (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 D₂over D₄receptors were ineffective, as well as the selective D₃receptor antagonist U 99194. Interestingly, (-)-raclopride (10^-6M) was able to block the neuroprotective effect of the atypical antipsychotic clozapine (10^-6M).</p> <p>Conclusion</p> <p>Taken together, these data suggest that D2-like receptors, particularly the D₄subtype, mediate the neuroprotective effects of antipsychotic drugs possibly through a ROS-independent, caspase-dependent mechanism.</p>