Imaging brain gene expression profiles by antipsychotics: region-specific action of amisulpride on postsynaptic density transcripts compared to haloperidol.

Abstract

Induction of motor disorders is considered the clinical landmark differentiating typical from atypical antipsychotics, and has been mainly correlated to dopamine D2 receptors blockade in striatum. This view is challenged by benzamides, such as amisulpride, which display low liability for motor side effects despite being D2/D3 receptors high-affinity blocking agents. These effects have been explained with the prominent presynaptic action of amisulpride or with the fast dissociation at D2 receptors, but there is scarce information on the effects of amisulpride on postsynaptic signaling. We carried out a molecular imaging study of gene expression after acute administration of haloperidol (0.8 mg/kg), amisulpride (10 or 35 mg/kg), or vehicle, focusing on postsynaptic genes that are key regulators of synaptic plasticity, such as Arc, c-fos, Zif-268, Norbin, Homer. The last one has been associated to schizophrenia both in clinical and preclinical studies, and is differentially induced by antipsychotics with different D2 receptors affinity. Topography of gene expression revealed that amisulpride, unlike haloperidol, triggers transcripts expression peak in medial striatal regions. Correlation analysis of gene expression revealed a prevalent correlated gene induction within motor corticostriatal regions by haloperidol and a more balanced gene induction within limbic and motor corticostriatal regions by amisulpride. Despite the selective dopaminergic profile of both compounds, our results demonstrated a differential modulation of postsynaptic molecules by amisulpride and haloperidol, the former impacting preferentially medial regions of striatum whereas the latter inducing strong gene expression in lateral regions. Thus, we provided a possible molecular profile of amisulpride, putatively explaining its "atypical atypicality".

• Authors: Andrea de Bartolomeis, Federica Marmo, Elisabetta Filomena Buonaguro, Rodolfo Rossi, Carmine Tomasetti, Felice Iasevoli
• Journal: European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology (Eur Neuropsychopharmacol) Vol. 23 Issue 11 Pg. 1516-29 (Nov 2013) ISSN: 1873-7862 [Electronic] Netherlands
• PMID: 23357084 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Elsevier B.V. and ECNP. All rights reserved.

Chemical References

• Antipsychotic Agents
• Dopamine Antagonists
• Sulpiride
• Amisulpride
• Haloperidol

Topics

• Amisulpride
• Animals
• Antipsychotic Agents (pharmacology)
• Cerebral Cortex (drug effects, metabolism)
• Corpus Striatum (drug effects, metabolism)
• Dopamine Antagonists (pharmacology)
• Dose-Response Relationship, Drug
• Functional Neuroimaging
• Gene Expression Profiling
• Genes, Immediate-Early (drug effects)
• Haloperidol (pharmacology)
• Limbic System (drug effects, metabolism)
• Male
• Organ Specificity (drug effects)
• Post-Synaptic Density (drug effects, genetics)
• Rats
• Sulpiride (analogs & derivatives, pharmacology)