Clozapine induction of ERK1/2 cell signalling via the EGF receptor in mouse prefrontal cortex and striatum is distinct from other antipsychotic drugs.

Treatment resistance remains a major obstacle in schizophrenia, with antipsychotic drugs (APDs) being ineffective in about one third of cases. Poor response to standard therapy leaves the APD clozapine as the only effective treatment for many patients. The reason for the superior efficacy of clozapine is unknown, but as we have proposed previously it may involve modulation of neuroplasticity and connectivity through induction of interconnected mitogenic signalling pathways. These include the mitogen-activated protein kinase-extracellular signal regulated kinase (MAPK-ERK) cascade and epidermal growth factor (EGF)/ErbB systems. Clozapine, distinct from other APDs, induced initial inhibition and subsequent activation of the ERK response in prefrontal cortical (PFC) neurons in vitro and in vivo, an action mediated by the EGF receptor (ErbB1). Here we examine additionally the striatum of C57Bl/6 mice to determine if clozapine, olanzapine, and haloperidol differentially regulate the ERK1/2 pathway in a region or time-specific manner conditional on the EGF receptor. Following acute treatment, only clozapine caused delayed striatal ERK phosphorylation through EGF receptor phosphorylation (tyrosine 1068 site) and MEK that paralleled cortical ERK phosphorylation. Olanzapine induced initial pERK1-specific blockade and an elevation 24-h later in PFC but had no effect in the striatum. By contrast, haloperidol significantly stimulated pERK1 in striatum for up to 8 h, but exerted limited effect in PFC. Clozapine but not olanzapine or haloperidol recruited the EGF receptor to signal to ERK. These in-vivo data reinforce our previous findings that clozapine's action may be uniquely linked to the EGF signalling system, potentially contributing to its distinctive clinical profile.