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.