Atypical neuroleptics stimulate neurogenesis in adult rat brain

Schizophrenia has been treated effectively with atypical neuroleptics without serious side effects. We have shown previously that long-term treatment with atypical neuroleptics is correlated with an improvement of cognition in adult rats. We report here that atypical neuroleptics stimulate a 2- to 3-fold increase in newly divided cells in the subventricular zone in the rat and that some of these new cells in the subventricular zone and hippocampus also express a neuronal marker. We used bromodeoxyuridine (BrdU) to identify newly divided cells and confirmed the observation with antibody to a cell-cycle-specific, endogenous proliferating cell nuclear antigen (PCNA). Identification of BrdU-positive cells in the anterior subventricular zone (SVZa) particularly in rats treated with the atypical neuroleptics but not in those in the haloperidol-treated and control rats, suggests increased rostral migratory stream (RMS) cell traffic to replenish neurons in the olfactory bulb. Expression of a neuronal marker, NeuN, in BrdU-positive cells in rats treated with atypical neuroleptics, also suggests that these compounds may modulate in vivo differentiation of neuronal progenitor cells even within a day of BrdU injection. Our results indicate that atypical neuroleptics have a mechanism of action other than the previously proposed mechanisms, which might explain their role in improved cognition in animal and in schizophrenic patients. If substantiated by future studies, our findings may lead to an expanded use of atypical neuroleptics in other neurodegenerative diseases to stimulate neuronal replacement and repair.