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Modulation by chronic antipsychotic administration of PKA- and GSK3β-mediated pathways and the NMDA receptor in rat ventral midbrain

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Abstract

Rationale

Antipsychotics exert therapeutic effects by modulating various cellular signalling pathways and several types of receptors, including PKA- and GSK3β-mediated signalling pathways, and NMDA receptors. The ventral midbrain, mainly containing the ventral tegmental area (VTA) and substantia nigra (SN), are the nuclei with dopamine origins in the brain, which are also involved in the actions of antipsychotics. Whether antipsychotics can modulate these cellular pathways in the ventral midbrain is unknown.

Objective

This study aims to investigate the effects of antipsychotics, including aripiprazole (a dopamine D2 receptor (D2R) partial agonist), bifeprunox (a D2R partial agonist), and haloperidol (a D2R antagonist) on the PKA- and GSK3β-mediated pathways and NMDA receptors in the ventral midbrain.

Methods

Male rats were orally administered aripiprazole (0.75 mg/kg, t.i.d. (ter in die)), bifeprunox (0.8 mg/kg, t.i.d.), haloperidol (0.1 mg/kg, t.i.d.) or vehicle for either 1 week or 10 weeks. The levels of PKA, p-PKA, Akt, p-Akt, GSK3β, p-GSK3β, Dvl-3, β-catenin, and NMDA receptor subunits in the ventral midbrain were assessed by Western Blots.

Results

The results showed that chronic antipsychotic treatment with aripiprazole selectively increased PKA activity in the VTA. Additionally, all three drugs elevated the activity of the Akt–GSK3β signalling pathway in a time-dependent manner, while only aripiprazole stimulated the Dvl-3–GSK3β–β-catenin signalling pathway in the SN. Furthermore, chronic administration with both aripiprazole and haloperidol decreased the expression of NMDA receptors.

Conclusion

This study suggests that activating PKA- and GSK3β-mediated pathways and downregulating NMDA receptor expression in the ventral midbrain might contribute to the clinical effects of antipsychotics.

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Acknowledgments

We would like to thank Dr. Jiamei Lian and Dr. Michael De-Santis for their technical assistance.

Funding

This study was supported by the Australian National Health and Medical Research Council project grant (APP1008473) to Chao Deng. Bo Pan was supported by the Natural Science Foundation of the Higher Education Institutions of Jiangsu Province, China (17KJB310018), the China Postdoctoral Science Foundation (2018 M632401), and the Natural Science Foundation of Jiangsu Province of China (BK20171290).

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Authors and Affiliations

  1. The Key Laboratory of Syndrome Differentiation and Treatment of Gastric Cancer of the State Administration of Traditional Chinese Medicine, Yangzhou University Medical College, Yangzhou, 225001, China

    Bo Pan

  2. Department of Pharmacy, Yangzhou University Medical College, Yangzhou, 225001, China

    Bo Pan

  3. School of Medicine, University of Wollongong, Wollongong, NSW, 2522, Australia

    Bo Pan & Chao Deng

  4. Antipsychotic Research Laboratory, Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong, NSW, 2522, Australia

    Bo Pan & Chao Deng

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  1. Bo Pan
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  2. Chao Deng
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Correspondence to Chao Deng.

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All experimental procedures were approved by the Animal Ethics Committee (AE11/02) of the University of Wollongong and complied with the Australian Code of Practice for the Care and Use of Animals for Scientific Purposes (2004).

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The authors declare that they have no conflict of interest.

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Pan, B., Deng, C. Modulation by chronic antipsychotic administration of PKA- and GSK3β-mediated pathways and the NMDA receptor in rat ventral midbrain. Psychopharmacology 236, 2687–2697 (2019). https://doi.org/10.1007/s00213-019-05243-x

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