title: Asenapine exerts distinctive regional effects on ionotropic glutamate receptor subtypes in rat brain.
abstract: Asenapine, a new pyschopharmacologic agent being developed for the treatment of schizophrenia and bipolar disorder, has a unique human receptor binding signature with strong affinity for dopaminergic, alpha-adrenergic, and, in particular, serotonergic receptors raising the possibility of interactions with glutamatergic receptors. Changes in ionotropic glutamate (Glu) N-methyl-D-aspartic acid (NMDA) receptors and 2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)propionic acid (AMPA) receptors in rat forebrain regions were quantified after repeated administration of multiple doses of asenapine (0.03, 0.1, or 0.3 mg/kg, subcutaneous, twice/day) or vehicle for 4 weeks. Brain sections were collected from the medial prefrontal cortex (mPFC), dorsolateral frontal cortex, caudate putamen (CPu), nucleus accumbens (NAc), and hippocampus (HIP), and processed for in vitro receptor autoradiography. Four weeks of treatment with 0.03, 0.1, or 0.3 mg/kg of asenapine significantly (P < 0.01) decreased binding of [3H]MK-801 to NMDA/MK-801 modulatory sites in NAc (by 27%, 29%, and 26%, respectively), medial CPu (by 25%, 28%, and 24%), and lateral CPu (by 24%, 31%, and 26%). In contrast, the same doses of asenapine did not alter binding of [3H]glycine to NMDA/glycine modulatory sites in any of the brain regions examined. [3H]AMPA binding to AMPA receptors was selectively and significantly (P < 0.001) elevated in hippocampal CA(1) (41%) and CA(3) (40%) regions but only at the highest dose tested. These results indicate that chronic treatment with asenapine has region-specific and dose-dependent effects on ionotropic Glu-receptor subtypes in rat forebrain, which might contribute to the unique psychopharmacologic properties of asenapine.
authors.affiliation: Mailman Research Center, McLean Division of Massachusetts General Hospital, Belmont, Massachusetts 02478, USA. ftarazi@hms.harvard.edu
authors.forename: Frank I
authors.initials: FI
authors.lastname: Tarazi
authors.forename: Yong Kee
authors.initials: YK
authors.lastname: Choi
authors.forename: Matthew
authors.initials: M
authors.lastname: Gardner
authors.forename: Erik H F
authors.initials: EH
authors.lastname: Wong
authors.forename: Brian
authors.initials: B
authors.lastname: Henry
authors.forename: Mohammed
authors.initials: M
authors.lastname: Shahid
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001345:Autoradiography / Q000379:methods; D001665:Binding Sites / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D001923:Brain Chemistry / Q000187:drug effects; D003986:Dibenzocycloheptenes; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005998:Glycine / Q000494:pharmacology; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology*; D008297:Male; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000187:drug effects*; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects*; D012044:Regression Analysis; D014316:Tritium / Q000494:pharmacology
chemical_list: D014150:Antipsychotic Agents; D003986:Dibenzocycloheptenes; D018691:Excitatory Amino Acid Antagonists; D006576:Heterocyclic Compounds, 4 or More Rings; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; D014316:Tritium; D016291:Dizocilpine Maleate; C522667:asenapine; D005998:Glycine