title: Regulation of postsynaptic plasticity genes' expression and topography by sustained dopamine perturbation and modulation by acute memantine: relevance to schizophrenia.
abstract: A relevant role for dopamine-glutamate interaction has been reported in the pathophysiology and treatment of psychoses. Dopamine and glutamate may interact at multiple levels, including the glutamatergic postsynaptic density (PSD), an electron-dense thickening that has gained recent attention as a switchboard of dopamine-glutamate interactions and for its role in synaptic plasticity. Recently, glutamate-based strategies, such as memantine add-on to antipsychotics, have been proposed for refractory symptoms of schizophrenia, e.g. cognitive impairment. Both antipsychotics and memantine regulate PSD transcripts but sparse information is available on memantine's effects under dopamine perturbation. We tested gene expression changes of the Homer1 and PSD-95 PSD proteins in models of sustained dopamine perturbation, i.e. subchronic treatment by: a) GBR-12909, a dopamine receptor indirect agonist; b) haloperidol, a D2R antagonist; c) SCH-23390, a dopamine D1 receptor (D1R) antagonist; and d) SCH-23390+haloperidol. On the last day of treatment, rats were acutely treated with vehicle or memantine. The Homer1a immediate-early gene was significantly induced by haloperidol and by haloperidol+SCH-23390. The gene was not induced by SCH-23390 per se or by GBR-12909. Expression of the constitutive genes Homer1b/c and PSD-95 was less affected by these dopaminergic paradigms. Acute memantine administration significantly increased Homer1a expression by the dopaminergic compounds used herein. Both haloperidol and haloperidol+SCH-23390 shifted Homer1a/Homer1b/c ratio of expression toward Homer1a. This pattern was sharpened by acute memantine. Dopaminergic compounds and acute memantine also differentially affected topographic distribution of gene expression and coordinated expression of Homer1a among cortical-subcortical regions. These results indicate that dopaminergic perturbations may affect glutamatergic signaling in different directions. Memantine may help partially revert dopamine-mediated glutamatergic dysfunctions.
authors.affiliation: Laboratory of Molecular and Translational Psychiatry, Department of Neuroscience, University School of Medicine "Federico II", Naples, Italy.
authors.forename: Felice
authors.initials: F
authors.lastname: Iasevoli
authors.affiliation: Laboratory of Molecular and Translational Psychiatry, Department of Neuroscience, University School of Medicine "Federico II", Naples, Italy.
authors.forename: Elisabetta F
authors.initials: EF
authors.lastname: Buonaguro
authors.affiliation: Laboratory of Molecular and Translational Psychiatry, Department of Neuroscience, University School of Medicine "Federico II", Naples, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Sarappa
authors.affiliation: Laboratory of Molecular and Translational Psychiatry, Department of Neuroscience, University School of Medicine "Federico II", Naples, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Marmo
authors.affiliation: Laboratory of Molecular and Translational Psychiatry, Department of Neuroscience, University School of Medicine "Federico II", Naples, Italy.
authors.forename: Gianmarco
authors.initials: G
authors.lastname: Latte
authors.affiliation: Laboratory of Molecular and Translational Psychiatry, Department of Neuroscience, University School of Medicine "Federico II", Naples, Italy.
authors.forename: Rodolfo
authors.initials: R
authors.lastname: Rossi
authors.affiliation: Medical Affairs & Phase IV Clinical Affairs, Lundbeck Pharmaceutical Services LLC, Deerfield, IL, United States.
authors.forename: Anna
authors.initials: A
authors.lastname: Eramo
authors.affiliation: Laboratory of Molecular and Translational Psychiatry, Department of Neuroscience, University School of Medicine "Federico II", Naples, Italy.
authors.forename: Carmine
authors.initials: C
authors.lastname: Tomasetti
authors.affiliation: Laboratory of Molecular and Translational Psychiatry, Department of Neuroscience, University School of Medicine "Federico II", Naples, Italy. Electronic address: adebarto@unina.it.
authors.forename: Andrea
authors.initials: A
authors.lastname: de Bartolomeis
mesh_terms: D000818:Animals; D001552:Benzazepines / Q000494:pharmacology; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism*; D000076122:Disks Large Homolog 4 Protein; D004298:Dopamine / Q000378:metabolism*; D015259:Dopamine Agents / Q000494:pharmacology*; D018492:Dopamine Antagonists / Q000494:pharmacology; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D006220:Haloperidol / Q000494:pharmacology; D000072233:Homer Scaffolding Proteins; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008297:Male; D008559:Memantine / Q000494:pharmacology*; D008565:Membrane Proteins / Q000378:metabolism*; D010879:Piperazines / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D011897:Random Allocation; D017207:Rats, Sprague-Dawley; D012559:Schizophrenia / Q000188:drug therapy / Q000503:physiopathology
chemical_list: D001552:Benzazepines; D002352:Carrier Proteins; D000076122:Disks Large Homolog 4 Protein; C501449:Dlg4 protein, rat; D015259:Dopamine Agents; D018492:Dopamine Antagonists; D018765:Dopamine Uptake Inhibitors; D000072233:Homer Scaffolding Proteins; C000606624:Homer1 protein, rat; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D010879:Piperazines; D012333:RNA, Messenger; C534628:SCH 23390; C043425:vanoxerine; D006220:Haloperidol; D004298:Dopamine; D008559:Memantine
keywords: Antipsychotics; Homer1; NMDA receptor; PSD-95; Treatment resistant schizophrenia