Modulation by chronic antipsychotic administration of PKA- and GSK3β-mediated pathways and the NMDA receptor in rat ventral midbrain
- 146 Downloads
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.
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.
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.
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.
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.
KeywordsAntipsychotics Ventral midbrain PKA GSK3β NMDA receptor
We would like to thank Dr. Jiamei Lian and Dr. Michael De-Santis for their technical assistance.
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).
Compliance with ethical standards
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).
Conflict of interest
The authors declare that they have no conflict of interest.
- (Administration) FUSFaD (2005) Guidance for industry on estimating the maximum safe starting dose in initial clinical trials for therapeutics in adult healthy volunteers. In: Services USDoHaH, Administration FaD, (CDER) CfDEaR (eds) Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers, Rockville, Maryland, USAGoogle Scholar
- Allen JA, Yost JM, Setola V, Chen X, Sassano MF, Chen M, Peterson S, Yadav PN, Huang XP, Feng B, Jensen NH, Che X, Bai X, Frye SV, Wetsel WC, Caron MG, Javitch JA, Roth BL, Jin J (2011) Discovery of beta-arrestin-biased dopamine D2 ligands for probing signal transduction pathways essential for antipsychotic efficacy. Proc Natl Acad Sci U S A 108:18488–18493CrossRefGoogle Scholar
- Dwivedi Y, Rizavi HS, Pandey GN (2002) Differential effects of haloperidol and clozapine on [(3)H]cAMP binding, protein kinase A (PKA) activity, and mRNA and protein expression of selective regulatory and catalytic subunit isoforms of PKA in rat brain. J Pharmacol Exp Ther 301:197–209CrossRefGoogle Scholar
- Ginovart N, Kapur S (2012) Role of dopamine D(2) receptors for antipsychotic activity. Handb Exp Pharmacol:27–52Google Scholar
- Lindgren N, Usiello A, Goiny M, Haycock J, Erbs E, Greengard P, Hokfelt T, Borrelli E, Fisone G (2003) Distinct roles of dopamine D2L and D2S receptor isoforms in the regulation of protein phosphorylation at presynaptic and postsynaptic sites. Proc Natl Acad Sci U S A 100:4305–4309CrossRefGoogle Scholar
- Paxinos G, Watson C (2005) The rat brain in stereotaxic coordinates. Elsevier Academic Press, San DiegoGoogle Scholar
- Roth BL, Driscol J (2018) PDSP Ki database Psychoactive Drug Screening Program (PDSP). University of North Carolina at Chapel Hill and the United States National Institute of Mental HealthGoogle Scholar
- Strait KA, Kuczenski R (1986) Dopamine autoreceptor regulation of the kinetic state of striatal tyrosine hydroxylase. Mol Pharmacol 29:561–569Google Scholar