Abstract
BACKGROUND: The dorsal raphe nucleus (DRN) is the origin of the 5-HT neurotransmission pathways. The 5-HT, dopamine D2, GABA, and NMDA receptors, as well as the cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA) and G protein-independent protein kinase B (PKB/Akt)-glycogen synthase kinase 3β (GSK3β) signaling, are involved in the pathophysiology of schizophrenia and are modulated by antipsychotics. However, their pathological changes and antipsychotic modulations in the DRN are not well understood in schizophrenia. OBJECTIVES: This study explored effects of antipsychotics on NMDA and GABA(A) receptors, as well as PKA, AKT-GSK3β, cAMP-responsive element-binding protein 1 (CREB1), and disheveled (Dvl)-β-catenin signaling in the DRN using a maternal immune activation rat model. METHODS: Prenatal polyriboinosinic-polyribocytidylic acid (Poly I:C) exposure was delivered at gestational Day 15. Female rats were treated with risperidone, olanzapine, or vehicle from postnatal day 70 for 35 days. RESULTS: Prenatal Poly I:C exposure increased mRNA expression of NMDA receptor Grin2a/2b subunits, the GABA(A) receptor β3 subunit, glutamic acid decarboxylase 1 (GAD1), AKT1/3, and GSK3β in the DRN. Antipsychotics significantly increased the mRNA expression of PKA, CREB1, β-catenin, GSK3β, and Grin2d subunits in the DRN of Poly I:C rats. Prenatal Poly I:C exposure led to decreased expression of GAD2, which was partially reversed antipsychotics. CONCLUSION: This study suggests that prenatal Poly I:C exposure and antipsychotics differentially modulate NMDA and GABA(A) receptors, as well as AKT-GSK3β, PKA-CREB1, and Dvl-β-catenin signaling in the DRN of rats. Poly I:C mainly influenced the AKT-GSK3β signaling, while antipsychotics modulated the AKT-GSK3β, PKA-CREB1, and Dvl-GSK3β-β-catenin signaling pathways in the DRN.