title: Change in expression of vesicular protein synapsin II by chronic treatment with D2 allosteric modulator PAOPA.
abstract: The hallmark symptoms of schizophrenia include profound disturbances in thought, perception, cognition etc., which negatively impacts an individual's quality of life. Current antipsychotic drugs are not effective in treating all symptoms of this disorder, and often cause severe movement and metabolic side effects. Consequently, there remains a strong impetus to develop safer and more efficacious therapeutics for patients, as well as elucidating the etiology of schizophrenia. Previous work in our lab has introduced a novel candidate for the treatment of this disease: the dopamine D2 receptor (D2R) allosteric modulator, 3(R)-[(2(S)-pyrrolidinylcarbonyl)amino]-2-oxo-1-pyrrolidineacetamide (PAOPA). We have previously shown that PAOPA, by selectively modulating D2R, can ameliorate schizophrenia-like symptoms in animal models, although the precise mechanism is presently not understood. Synapsin II is a presynaptic vesicular protein which has been strongly implicated in schizophrenia, as it is reduced in the prefrontal cortex of patients, and knockdown of this protein elicits schizophrenia-like phenotypes in animal models. Given the therapeutic effects of PAOPA and the role of synapsin II in schizophrenia, the objective of this study was to investigate the effect of chronic administration of PAOPA (45 days) on neuronal synapsin II protein expression in rodents. Immunoblot results revealed that the synapsin IIa, but not the IIb isoform, was increased in the dopaminergic regions of the striatum, nucleus accumbens, and medial prefrontal cortex. The results of this study implicate a role for modulation of synapsin II as a possible therapeutic mechanism of action for potential antipsychotic drug PAOPA.
authors.affiliation: Department of Psychiatry and Behavioural Neurosciences, McMaster University, 1200 Main St. W., Hamilton, ON, Canada L8N 3Z5.
authors.forename: Dipannita
authors.initials: D
authors.lastname: Basu
authors.affiliation: Department of Psychiatry and Behavioural Neurosciences, McMaster University, 1200 Main St. W., Hamilton, ON, Canada L8N 3Z5.
authors.forename: Yuxin
authors.initials: Y
authors.lastname: Tian
authors.affiliation: Department of Psychiatry and Behavioural Neurosciences, McMaster University, 1200 Main St. W., Hamilton, ON, Canada L8N 3Z5.
authors.forename: Patricia
authors.initials: P
authors.lastname: Hui
authors.affiliation: Department of Psychiatry and Behavioural Neurosciences, McMaster University, 1200 Main St. W., Hamilton, ON, Canada L8N 3Z5.
authors.forename: Jayant
authors.initials: J
authors.lastname: Bhandari
authors.affiliation: Department of Medicinal Chemistry, University of Minnesota, 308 Harvard Street SE, Minneapolis, MN 55455, USA.
authors.forename: Rodney L
authors.initials: RL
authors.lastname: Johnson
authors.affiliation: Department of Psychiatry and Behavioural Neurosciences, McMaster University, 1200 Main St. W., Hamilton, ON, Canada L8N 3Z5. Electronic address: mishrar@mcmaster.ca.
authors.forename: Ram K
authors.initials: RK
authors.lastname: Mishra
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology; D015153:Blotting, Western; D002531:Cerebellum / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism; D011760:Pyrrolidinones / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016704:Synapsins / Q000378:metabolism*
chemical_list: D014150:Antipsychotic Agents; D011760:Pyrrolidinones; D016704:Synapsins; C067487:3-(N-prolylamine)-2-oxo-1-pyrrolidineacetamide
keywords: Allosteric drugs; Antipsychotic drug; Dopamine D2 receptor; Schizophrenia; Synapsin II