Bo Pan1,2,3,4, Chao Deng5,6. 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. 2. Department of Pharmacy, Yangzhou University Medical College, Yangzhou, 225001, China. 3. School of Medicine, University of Wollongong, Wollongong, NSW, 2522, Australia. 4. Antipsychotic Research Laboratory, Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong, NSW, 2522, Australia. 5. School of Medicine, University of Wollongong, Wollongong, NSW, 2522, Australia. chao@uow.edu.au. 6. Antipsychotic Research Laboratory, Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong, NSW, 2522, Australia. chao@uow.edu.au.
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.
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.
Authors: Taylor Moran-Gates; Lu Gan; Young Shik Park; Kehong Zhang; Ross J Baldessarini; Frank I Tarazi Journal: Synapse Date: 2006-02 Impact factor: 2.562
Authors: Niklas Lindgren; Alessandro Usiello; Michel Goiny; John Haycock; Eric Erbs; Paul Greengard; Tomas Hokfelt; Emiliana Borrelli; Gilberto Fisone Journal: Proc Natl Acad Sci U S A Date: 2003-03-21 Impact factor: 11.205