The Dopamine Allosteric Agent, PAOPA, Demonstrates Therapeutic Potential in the Phencyclidine NMDA Pre-clinical Rat Model of Schizophrenia
PAOPA, a potent analog of prolyl-leucyl-glycinamide, has shown therapeutic potential at the preclinical stage for dopaminergic related illnesses, including animal models of schizophrenia, Parkinson’s disease and haloperidol-induced extrapyramidal movement disorders. PAOPA’s unique allosteric mechani...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2018-12-01
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| Series: | Frontiers in Behavioral Neuroscience |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fnbeh.2018.00302/full |
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| author | Ritesh P. Daya Jayant Bhandari Sharnpreet K. Kooner Joella Ho Christopher D. Rowley Nicholas A. Bock Troy Farncombe Ram K. Mishra |
| author_facet | Ritesh P. Daya Jayant Bhandari Sharnpreet K. Kooner Joella Ho Christopher D. Rowley Nicholas A. Bock Troy Farncombe Ram K. Mishra |
| author_sort | Ritesh P. Daya |
| collection | DOAJ |
| description | PAOPA, a potent analog of prolyl-leucyl-glycinamide, has shown therapeutic potential at the preclinical stage for dopaminergic related illnesses, including animal models of schizophrenia, Parkinson’s disease and haloperidol-induced extrapyramidal movement disorders. PAOPA’s unique allosteric mechanism and dopamine D2 receptor specificity provide a unique composition of properties for the development of potential therapeutics for neuropsychiatric illnesses. We sought to investigate PAOPA’s therapeutic prospects across the spectrum of schizophrenia-like symptoms represented in the established phencyclidine-induced rat model of schizophrenia, (5 mg/kg PCP twice daily for 7 days, followed by 7 days of drug withdrawal). PAOPA was assessed for its effect on brain metabolic activity and across a battery of behavioral tests including, hyperlocomotion, social withdrawal, sensorimotor gating, and novel object recognition. PAOPA showed therapeutic efficacy in behavioral paradigms representing the negative (social withdrawal) and cognitive-like (novel object recognition) symptoms of schizophrenia. Interestingly, some behavioral indices associated with the positive symptoms of schizophrenia that were ameliorated in PAOPA’s prior examination in the amphetamine-sensitized model of schizophrenia were not ameliorated in the PCP model; suggesting that the deficits induced by amphetamine and PCP—while phenotypically similar—are mechanistically different and that PAOPA’s effects are restricted to certain mechanisms and systems. These studies provide insight on the potential use of PAOPA for the safe and effective treatment of schizophrenia. |
| first_indexed | 2024-12-20T19:52:38Z |
| format | Article |
| id | doaj.art-35e1aeacea904b069f84bd70655ba3fc |
| institution | Directory Open Access Journal |
| issn | 1662-5153 |
| language | English |
| last_indexed | 2024-12-20T19:52:38Z |
| publishDate | 2018-12-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Behavioral Neuroscience |
| spelling | doaj.art-35e1aeacea904b069f84bd70655ba3fc2022-12-21T19:28:14ZengFrontiers Media S.A.Frontiers in Behavioral Neuroscience1662-51532018-12-011210.3389/fnbeh.2018.00302423899The Dopamine Allosteric Agent, PAOPA, Demonstrates Therapeutic Potential in the Phencyclidine NMDA Pre-clinical Rat Model of SchizophreniaRitesh P. Daya0Jayant Bhandari1Sharnpreet K. Kooner2Joella Ho3Christopher D. Rowley4Nicholas A. Bock5Troy Farncombe6Ram K. Mishra7Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, ON, CanadaDepartment of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, ON, CanadaDepartment of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, ON, CanadaDepartment of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, ON, CanadaDepartment of Psychology, Neuroscience and Behaviour, McMaster University, Hamilton, ON, CanadaDepartment of Psychology, Neuroscience and Behaviour, McMaster University, Hamilton, ON, CanadaDepartment of Radiology, McMaster University, Hamilton, ON, CanadaDepartment of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, ON, CanadaPAOPA, a potent analog of prolyl-leucyl-glycinamide, has shown therapeutic potential at the preclinical stage for dopaminergic related illnesses, including animal models of schizophrenia, Parkinson’s disease and haloperidol-induced extrapyramidal movement disorders. PAOPA’s unique allosteric mechanism and dopamine D2 receptor specificity provide a unique composition of properties for the development of potential therapeutics for neuropsychiatric illnesses. We sought to investigate PAOPA’s therapeutic prospects across the spectrum of schizophrenia-like symptoms represented in the established phencyclidine-induced rat model of schizophrenia, (5 mg/kg PCP twice daily for 7 days, followed by 7 days of drug withdrawal). PAOPA was assessed for its effect on brain metabolic activity and across a battery of behavioral tests including, hyperlocomotion, social withdrawal, sensorimotor gating, and novel object recognition. PAOPA showed therapeutic efficacy in behavioral paradigms representing the negative (social withdrawal) and cognitive-like (novel object recognition) symptoms of schizophrenia. Interestingly, some behavioral indices associated with the positive symptoms of schizophrenia that were ameliorated in PAOPA’s prior examination in the amphetamine-sensitized model of schizophrenia were not ameliorated in the PCP model; suggesting that the deficits induced by amphetamine and PCP—while phenotypically similar—are mechanistically different and that PAOPA’s effects are restricted to certain mechanisms and systems. These studies provide insight on the potential use of PAOPA for the safe and effective treatment of schizophrenia.https://www.frontiersin.org/article/10.3389/fnbeh.2018.00302/fullallosteric modulatordopamineNMDAphencyclidinerat modelschizophrenia |
| spellingShingle | Ritesh P. Daya Jayant Bhandari Sharnpreet K. Kooner Joella Ho Christopher D. Rowley Nicholas A. Bock Troy Farncombe Ram K. Mishra The Dopamine Allosteric Agent, PAOPA, Demonstrates Therapeutic Potential in the Phencyclidine NMDA Pre-clinical Rat Model of Schizophrenia Frontiers in Behavioral Neuroscience allosteric modulator dopamine NMDA phencyclidine rat model schizophrenia |
| title | The Dopamine Allosteric Agent, PAOPA, Demonstrates Therapeutic Potential in the Phencyclidine NMDA Pre-clinical Rat Model of Schizophrenia |
| title_full | The Dopamine Allosteric Agent, PAOPA, Demonstrates Therapeutic Potential in the Phencyclidine NMDA Pre-clinical Rat Model of Schizophrenia |
| title_fullStr | The Dopamine Allosteric Agent, PAOPA, Demonstrates Therapeutic Potential in the Phencyclidine NMDA Pre-clinical Rat Model of Schizophrenia |
| title_full_unstemmed | The Dopamine Allosteric Agent, PAOPA, Demonstrates Therapeutic Potential in the Phencyclidine NMDA Pre-clinical Rat Model of Schizophrenia |
| title_short | The Dopamine Allosteric Agent, PAOPA, Demonstrates Therapeutic Potential in the Phencyclidine NMDA Pre-clinical Rat Model of Schizophrenia |
| title_sort | dopamine allosteric agent paopa demonstrates therapeutic potential in the phencyclidine nmda pre clinical rat model of schizophrenia |
| topic | allosteric modulator dopamine NMDA phencyclidine rat model schizophrenia |
| url | https://www.frontiersin.org/article/10.3389/fnbeh.2018.00302/full |
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