Role of the NRG1/ErbB4 and PI3K/AKT/mTOR signaling pathways in the anti-psychotic effects of aripiprazole and sertindole in ketamine-induced schizophrenia-like behaviors in rats
Dalia A. Nawwar, R. H. Sayed, H. Zaki
InflammoPharmacology July 25, 2022 DOI: 10.1007/s10787-022-01031-w (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Animal experiment (pharmacological study in rats) Peer reviewed |
|---|---|
| Population | Young male Wistar rats with ketamine-induced schizophrenia-like behavior |
| Interventions | Ketamine Aripiprazole Sertindole LY294002 |
| Dose | ketamine 30 mg/kg intraperitoneally; aripiprazole 3 mg/kg orally; sertindole 2.5 mg/kg orally; LY294002 25 μg/kg intrahippocampal |
| Duration | Ketamine for 5 consecutive days; aripiprazole or sertindole for 14 days; behavioral tests 24 hours after last injection |
| Measures | open field test, sucrose preference test, novel object recognition task, social interaction test |
| Topics | Esketamine Ketamine |
| Key findings | Aripiprazole and sertindole reduced ketamine-induced schizophrenia-like behaviors, oxidative stress, and neurotransmitter changes in rats, and increased NRG1/ErbB4 mRNA and PI3K/AKT/mTOR protein expression. Pre-injecting the PI3K inhibitor LY294002 abolished all drug effects, which the authors interpret as evidence that the antipsychotic effects are partly due to activation of these pathways. |
Abstract
Schizophrenia is a common mental disorder affecting patients’ thoughts, behavior, and cognition. Recently, the NRG1/ErbB4 signaling pathway emerged as a candidate therapeutic target for schizophrenia. This study investigates the effects of aripiprazole and sertindole on the NRG1/ErbB4 and PI3K/AKT/mTOR signaling pathways in ketamine-induced schizophrenia in rats. Young male Wistar rats received ketamine (30 mg/kg, intraperitoneally) for 5 consecutive days and aripiprazole (3 mg/kg, orally) or sertindole (2.5 mg/kg, orally) for 14 days. The proposed pathway was investigated by injecting LY294002 (a selective PI3K inhibitor) (25 μg/kg, intrahippocampal injection) 30 min before the drugs. Twenty-four hours after the last injection, animals were subjected to behavioral tests: the open field test, sucrose preference test, novel object recognition task, and social interaction test. Both aripiprazole and sertindole significantly ameliorated ketamine-induced schizophrenic-like behavior, as expected, because of their previously demonstrated antipsychotic activity. Besides, both drugs alleviated ketamine-induced oxidative stress and neurotransmitter level changes in the hippocampus. They also increased the gamma-aminobutyric acid and glutamate levels and glutamate decarboxylase 67 and parvalbumin mRNA expression in the hippocampus. Moreover, aripiprazole and sertindole increased the NRG1 and ErbB4 mRNA expression levels and PI3K, p-Akt, and mTOR protein expression levels. Interestingly, pre-injecting LY294002 abolished all the effects of the drugs. This study reveals that the antipsychotic effects of aripiprazole and sertindole are partly due to oxidative stress reduction as well as NRG1/ErbB4 and PI3K/AKT/mTOR signaling pathways activation. The NRG1/ErbB4 and PI3K signaling pathways may offer a new therapeutic approach for treating schizophrenia in humans.
Comparable studies
Other preclinical and animal studies on ketamine, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Rats | 2010 | Observational study | |
| Activation of Glutamatergic Neurotransmission by Ketamine: A Novel Step in the Pathway from NMDA Receptor Blockade to Dopaminergic and Cognitive Disruptions Associated with the Prefrontal Cortex Conscious rats | 1997 | Dose-response study with microdialysis and behavioral testing | |
| NMDAR inhibition-independent antidepressant actions of ketamine metabolites Mice | 2016 | Preclinical study | |
| The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N‐methyl‐aspartate Spinal neurons in decerebrate or pentobarbitone-anaesthetized cats and rats | 1983 | Experimental study | |
| R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects Mice | 2015 | Experimental study |
Citations in the library
Cited by 5
- Sex difference alters the behavioral and cognitive performance in a rat model of schizophrenia induced by sub-chronic ketamine. Journal of Psychiatric Research October 1, 2024
- Sigma-1 Receptor Activation by Fluvoxamine Ameliorates ER Stress, Synaptic Dysfunction and Behavioral Deficits in a Ketamine Model of Schizophrenia. Journal of Neuroimmune Pharmacology July 25, 2025
- Esketamine ameliorates depression-like behavior in mice via modulation of the NRG1-ErbB4 pathway. Frontiers in Psychiatry 2026
- LSD and ketamine in schizoaffective paranoid psychosis involving childhood and war trauma—a retrospective case study August 5, 2024
- Unraveling Cannabidiol's Dual Modulatory Role in Schizophrenia: Network Pharmacology and In Vivo Validation of Neuroinflammatory and Behavioral Modulation Molecular Neurobiology December 10, 2025
Cites 6
- Subanesthetic Effects of the Noncompetitive NMDA Antagonist, Ketamine, in Humans Archives of General Psychiatry March 1, 1994
- Effects of nitric oxide-related compounds in the acute ketamine animal model of schizophrenia BMC Neuroscience March 5, 2015
- Niacin mitigates blood-brain barrier tight junctional proteins dysregulation and cerebral inflammation in ketamine rat model of psychosis: Role of GPR109A receptor. Progress in Neuro-Psychopharmacology and Biological Psychiatry June 8, 2022
- Neuregulin signaling mediates the acute and sustained antidepressant effects of subanesthetic ketamine Translational Psychiatry February 24, 2021
- Vinpocetine halts ketamine-induced schizophrenia-like deficits in rats: impact on BDNF and GSK-3β/β-catenin pathway. Naunyn-Schmiedeberg's Archives of Pharmacology August 6, 2018
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