title: Progressive recruitment of cortical and striatal regions by inducible postsynaptic density transcripts after increasing doses of antipsychotics with different receptor profiles: insights for psychosis treatment.
abstract: Antipsychotics may modulate the transcription of multiple gene programs, including those belonging to postsynaptic density (PSD) network, within cortical and subcortical brain regions. Understanding which brain region is activated progressively by increasing doses of antipsychotics and how their different receptor profiles may impact such an activation could be relevant to better correlate the mechanism of action of antipsychotics both with their efficacy and side effects. We analyzed the differential topography of PSD transcripts by incremental doses of two antipsychotics: haloperidol, the prototypical first generation antipsychotic with prevalent dopamine D2 receptors antagonism, and asenapine, a second generation antipsychotic characterized by multiple receptors occupancy. We investigated the expression of PSD genes involved in synaptic plasticity and previously demonstrated to be modulated by antipsychotics: Homer1a, and its related interacting constitutive genes Homer1b/c and PSD95, as well as Arc, C-fos and Zif-268, also known to be induced by antipsychotics administration. We found that increasing acute doses of haloperidol induced immediate-early genes (IEGs) expression in different striatal areas, which were progressively recruited by incremental doses with a dorsal-to-ventral gradient of expression. Conversely, increasing acute asenapine doses progressively de-recruited IEGs expression in cortical areas and increased striatal genes signal intensity. These effects were mirrored by a progressive reduction in locomotor animal activity by haloperidol, and an opposite increase by asenapine. Thus, we demonstrated for the first time that antipsychotics may progressively recruit PSD-related IEGs expression in cortical and subcortical areas when administered at incremental doses and these effects may reflect a fine-tuned dose-dependent modulation of the PSD.
authors: Laboratory of Molecular and Translational Psychiatry, Department of Neuroscience, University Medical School of Naples Federico II, Italy. Electronic address: adebarto@unina.it.
authors: Andrea
authors: A
authors: de Bartolomeis
authors: Laboratory of Molecular and Translational Psychiatry, Department of Neuroscience, University Medical School of Naples Federico II, Italy.
authors: Felice
authors: F
authors: Iasevoli
authors: Laboratory of Molecular and Translational Psychiatry, Department of Neuroscience, University Medical School of Naples Federico II, Italy.
authors: Federica
authors: F
authors: Marmo
authors: Laboratory of Molecular and Translational Psychiatry, Department of Neuroscience, University Medical School of Naples Federico II, Italy.
authors: Elisabetta F
authors: EF
authors: Buonaguro
authors: Medical Affairs & Phase IV Clinical Affair. Lundbeck Pharmaceutical Services LLC, Deerfield, IL, United States.
authors: Anna
authors: A
authors: Eramo
authors: Laboratory of Molecular and Translational Psychiatry, Department of Neuroscience, University Medical School of Naples Federico II, Italy.
authors: Rodolfo
authors: R
authors: Rossi
authors: Laboratory of Molecular and Translational Psychiatry, Department of Neuroscience, University Medical School of Naples Federico II, Italy.
authors: Livia
authors: L
authors: Avvisati
authors: Laboratory of Molecular and Translational Psychiatry, Department of Neuroscience, University Medical School of Naples Federico II, Italy.
authors: Gianmarco
authors: G
authors: Latte
authors: Laboratory of Molecular and Translational Psychiatry, Department of Neuroscience, University Medical School of Naples Federico II, Italy.
authors: Carmine
authors: C
authors: Tomasetti
mesh_terms: D000386:AIDS-Related Complex / Q000235:genetics / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D000076122:Disks Large Homolog 4 Protein; D004305:Dose-Response Relationship, Drug; D051766:Early Growth Response Protein 1 / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D000072233:Homer Scaffolding Proteins; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D009043:Motor Activity / Q000187:drug effects; D016761:Oncogene Proteins v-fos / Q000235:genetics / Q000378:metabolism; D057907:Post-Synaptic Density / Q000187:drug effects* / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018709:Statistics, Nonparametric
chemical_list: D014150:Antipsychotic Agents; D002352:Carrier Proteins; D000076122:Disks Large Homolog 4 Protein; C501449:Dlg4 protein, rat; C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; D000072233:Homer Scaffolding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D016761:Oncogene Proteins v-fos; D012333:RNA, Messenger
keywords: Asenapine; Bipolar disorder; Haloperidol; Homer; Immediate-early genes; Schizophrenia