Quetiapine and aripiprazole signal differently to ERK, p90RSK and c-Fos in mouse frontal cortex and striatum: role of the EGF receptor

Avril Pereira,Betty Zhang,Peter Malcolm,Anthony Sugiharto-Winarno,Suresh Sundram

doi:10.1186/1471-2202-15-30

Abstract

BackgroundSignaling pathways outside dopamine D2 receptor antagonism may govern the variable clinical profile of antipsychotic drugs (APD) in schizophrenia. One postulated mechanism causal to APD action may regulate synaptic plasticity and neuronal connectivity via the extracellular signal-regulated kinase (ERK) cascade that links G-protein coupled receptors (GPCR) and ErbB growth factor signaling, systems disturbed in schizophrenia. This was based upon our finding that the low D2 receptor affinity APD clozapine induced initial down-regulation and delayed epidermal growth factor receptor (EGFR or ErbB1) mediated activation of the cortical and striatal ERK response in vivo distinct from olanzapine or haloperidol. Here we map whether the second generation atypical APDs aripiprazole and quetiapine affect the EGFR-ERK pathway and its substrates p90RSK and c-Fos in mouse brain, given their divergent agonist and antagonist properties on dopaminergic transmission, respectively.ResultsIn prefrontal cortex, aripiprazole triggered triphasic ERK phosphorylation that was EGFR-independent but had no significant effect in striatum. Conversely quetiapine did not alter cortical ERK signaling but elevated striatal ERK levels in an EGFR-dependent manner. Induction of ERK by aripiprazole did not affect p90RSK signaling but quetiapine decreased RSK phosphorylation within 1-hour of administration. The transcription factor c-Fos by comparison was a direct target of ERK phosphorylation induced by aripiprazole in cortex and quetiapine in striatum with protein levels in temporal alignment with that of ERK.ConclusionsThese data indicate that aripiprazole and quetiapine signal to specific nuclear targets of ERK, which for quetiapine occurs via an EGFR-linked mechanism, possibly indicating involvement of this system in its action.

Highlights

Signaling pathways outside dopamine Dopamine D2 receptors (D2) receptor antagonism may govern the variable clinical profile of antipsychotic drugs (APD) in schizophrenia
Effect of aripiprazole and quetiapine over 24 hours on extracellular signal-regulated kinase (ERK) phosphorylation in mouse prefrontal cortex and striatum Exposure to aripiprazole resulted in region-specific pERK1/2 levels decreased at min (pERK1)/2 findings with phosphorylation altered in the PFC
A marked increase in pERK1 activation was observed only at 240 min (F(9, 24) = 6.930, p < 0.0001; vehicle 100 ± 4% vs quetiapine 144 ± 6%,1 p < 0.01) with levels normalizing by 24 hr (Figure 1A) while phosphorylated ERK2 (pERK2) levels did not vary significantly between untreated and quetiapine treated mice at any time point (Figure 2B)

Summary

Introduction

Signaling pathways outside dopamine D2 receptor antagonism may govern the variable clinical profile of antipsychotic drugs (APD) in schizophrenia. Positron emission topography studies indicate that quetiapine rapidly disassociates from the D2 receptor producing normal physiological surges of dopamine in the nigrostriatal and tuberoinfundibular tracts of the brain, minimizing the risk of extrapyramidal side effects (EPS) and elevations in prolactin For both aripiprazole and quetiapine, effects on downstream ERK signaling that can regulate transcription factors such as Elk or CREB to shape gene expression, protein synthesis and receptor function is less well characterized. Whilst cortical and/or striatal ERK phosphorylation by aripiprazole and quetiapine integrate multiple signaling pathways to regulate neuronal processes relevant to the symptom domains of schizophrenia, there remains a paucity of data on the effects of these APDs on the expression of downstream proteins such as 90 kDa ribosomal s6 protein kinase (p90RSK) or c-fos, which potentially define their distinct clinical profiles

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