title: Switching antipsychotics: Imaging the differential effect on the topography of postsynaptic density transcripts in antipsychotic-naïve vs. antipsychotic-exposed rats.
abstract: The postsynaptic density (PSD) has been regarded as a functional switchboard at the crossroads of a dopamine-glutamate interaction, and it is putatively involved in the pathophysiology of psychosis. Indeed, it has been demonstrated that antipsychotics may modulate several PSD transcripts, such as PSD-95, Shank, and Homer. Despite switching antipsychotics is a frequent strategy to counteract lack of efficacy and/or side effect onset in clinical practice, no information is available on the effects of sequential treatments with different antipsychotics on PSD molecules. The aim of this study was to evaluate whether a previous exposure to a typical antipsychotic and a switch to an atypical one may affect the expression of PSD transcripts, in order to evaluate potential neurobiological correlates of this common clinical practice, with specific regards to putative synaptic plasticity processes. We treated male Sprague-Dawley rats intraperitoneally for 15days with haloperidol or vehicle, then from the sixteenth day we switched the animals to amisulpride or continued to treat them with vehicle or haloperidol for 15 additional days. In this way we got six first treatment/second treatment groups: vehicle/vehicle, vehicle/haloperidol, vehicle/amisulpride, haloperidol/vehicle, haloperidol/haloperidol, haloperidol/amisulpride. In this paradigm, we evaluated the expression of brain transcripts belonging to relevant and interacting PSD proteins, both of the Immediate-Early Gene (Homer1a, Arc) and the constitutive classes (Homer1b/c and PSD-95). The major finding was the differential effect of amisulpride on gene transcripts when administered in naïve vs. antipsychotic-pretreated rats, with modifications of the ratio between Homer1a/Homer1b transcripts and differential effects in cortex and striatum. These results suggest that the neurobiological effects on PSD transcripts of amisulpride, and possibly of other antipsychotics, may be greatly affected by prior antipsychotic treatments and may impact significantly on the switching procedure.
authors.affiliation: Laboratory of Molecular and Translational Psychiatry, Department of Neuroscience, School of Medicine, University "Federico II", Naples, Italy. Electronic address: adebarto@unina.it.
authors.forename: Andrea
authors.initials: A
authors.lastname: de Bartolomeis
authors.affiliation: Laboratory of Molecular and Translational Psychiatry, Department of Neuroscience, School of Medicine, University "Federico II", Naples, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Marmo
authors.affiliation: Laboratory of Molecular and Translational Psychiatry, Department of Neuroscience, School of Medicine, University "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, School of Medicine, University "Federico II", Naples, Italy.
authors.forename: Gianmarco
authors.initials: G
authors.lastname: Latte
authors.affiliation: Laboratory of Molecular and Translational Psychiatry, Department of Neuroscience, School of Medicine, University "Federico II", Naples, Italy.
authors.forename: Carmine
authors.initials: C
authors.lastname: Tomasetti
authors.affiliation: Laboratory of Molecular and Translational Psychiatry, Department of Neuroscience, School of Medicine, University "Federico II", Naples, Italy.
authors.forename: Felice
authors.initials: F
authors.lastname: Iasevoli
mesh_terms: D000077582:Amisulpride; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000378:metabolism; D000076122:Disks Large Homolog 4 Protein; D004351:Drug Resistance / Q000502:physiology; D057915:Drug Substitution; D015870:Gene Expression / Q000187:drug effects; D006220:Haloperidol / Q000494:pharmacology*; D000072233:Homer Scaffolding Proteins / Q000378:metabolism*; D007274:Injections, Intraperitoneal; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D057907:Post-Synaptic Density / Q000187:drug effects* / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D011897:Random Allocation; D017207:Rats, Sprague-Dawley; D013469:Sulpiride / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D014150:Antipsychotic Agents; D003598:Cytoskeletal Proteins; D000076122:Disks Large Homolog 4 Protein; C501449:Dlg4 protein, rat; D000072233:Homer Scaffolding Proteins; C000606624:Homer1 protein, rat; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; C092069:activity regulated cytoskeletal-associated protein; D013469:Sulpiride; D000077582:Amisulpride; D006220:Haloperidol
keywords: Amisulpride; Haloperidol; Homer; Treatment resistant schizophrenia