Differential Effects of Prenatal Poly I:C Exposure and Antipsychotics on NMDA/GABA Receptors and GSK3β-Mediated Signaling in the Dorsal Raphe Nucleus of Female Rats

IF 2.1 4区医学 Q3 PHARMACOLOGY & PHARMACY

Fundamental & Clinical Pharmacology Pub Date : 2025-06-25 DOI:10.1111/fcp.70033

Shiyan Chen, Jiamei Lian, Yueqing Su, Chao Deng

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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.

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产前Poly I:C暴露和抗精神病药物对雌性大鼠中缝背核NMDA/GABA受体和gsk3 β介导的信号传导的差异影响

中缝背核（DRN）是5-HT神经传递通路的起源。5-HT、多巴胺D2、GABA和NMDA受体以及环腺苷单磷酸(cAMP)-蛋白激酶A （PKA）和G蛋白独立蛋白激酶B (PKB/Akt)-糖原合成酶激酶3β (GSK3β)信号通路参与了精神分裂症的病理生理，并受到抗精神病药物的调节。然而，它们在精神分裂症中的病理改变和DRN的抗精神病调节作用尚不清楚。目的利用母体免疫激活大鼠模型，探讨抗精神病药物对DRN中NMDA和GABAA受体以及PKA、AKT-GSK3β、cAMP-responsive element-binding protein 1 （CREB1）和disheveled (Dvl)-β-catenin信号的影响。方法在妊娠第15天给予产前多核糖素-多核糖素（Poly I:C）暴露。雌性大鼠从出生后第70天开始分别给予利培酮、奥氮平或对照物治疗，持续35天。结果产前Poly I:C暴露增加了DRN中NMDA受体Grin2a/2b亚基、GABAA受体β3亚基、谷氨酸脱羧酶1 （GAD1）、AKT1/3和GSK3β mRNA的表达。抗精神病药物显著增加Poly I:C大鼠DRN中PKA、CREB1、β-catenin、GSK3β和Grin2d亚基的mRNA表达。产前Poly I:C暴露导致GAD2表达降低，部分逆转抗精神病药物的作用。结论产前Poly I:C暴露和抗精神病药物对大鼠DRN中NMDA和GABAA受体以及AKT-GSK3β、PKA-CREB1和Dvl-β-catenin信号通路的影响存在差异。Poly I:C主要影响AKT-GSK3β信号通路，而抗精神病药物则调节DRN中AKT-GSK3β、PKA-CREB1和Dvl-GSK3β-β-catenin信号通路。

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来源期刊

Fundamental & Clinical Pharmacology 医学-药学

CiteScore

5.30

自引率

6.90%

发文量

111

审稿时长

6-12 weeks

期刊介绍： Fundamental & Clinical Pharmacology publishes reports describing important and novel developments in fundamental as well as clinical research relevant to drug therapy. Original articles, short communications and reviews are published on all aspects of experimental and clinical pharmacology including: Antimicrobial, Antiviral Agents Autonomic Pharmacology Cardiovascular Pharmacology Cellular Pharmacology Clinical Trials Endocrinopharmacology Gene Therapy Inflammation, Immunopharmacology Lipids, Atherosclerosis Liver and G-I Tract Pharmacology Metabolism, Pharmacokinetics Neuropharmacology Neuropsychopharmacology Oncopharmacology Pediatric Pharmacology Development Pharmacoeconomics Pharmacoepidemiology Pharmacogenetics, Pharmacogenomics Pharmacovigilance Pulmonary Pharmacology Receptors, Signal Transduction Renal Pharmacology Thrombosis and Hemostasis Toxicopharmacology Clinical research, including clinical studies and clinical trials, may cover disciplines such as pharmacokinetics, pharmacodynamics, pharmacovigilance, pharmacoepidemiology, pharmacogenomics and pharmacoeconomics. Basic research articles from fields such as physiology and molecular biology which contribute to an understanding of drug therapy are also welcomed.