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Asenapine exerts distinctive regional effects on ionotropic glutamate receptor subtypes in rat brain
Author(s) -
Tarazi Frank I.,
Choi Yong Kee,
Gardner Matthew,
Wong Erik H.F.,
Henry Brian,
Shahid Mohammed
Publication year - 2009
Publication title -
synapse
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.809
H-Index - 106
eISSN - 1098-2396
pISSN - 0887-4476
DOI - 10.1002/syn.20618
Subject(s) - ionotropic effect , ampa receptor , asenapine , chemistry , nmda receptor , glutamatergic , glutamate receptor , nucleus accumbens , pharmacology , long term depression , receptor , medicine , endocrinology , biochemistry , biology , lithium (medication) , bipolar disorder
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, α‐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 [ 3 H]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 [ 3 H]glycine to NMDA/glycine modulatory sites in any of the brain regions examined. [ 3 H]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. Synapse 63:413–420, 2009. © 2009 Wiley‐Liss, Inc.