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.

Repeated effects of asenapine on adrenergic and cholinergic muscarinic receptors

“…In this regard, the effects of asenapine on muscarinic receptors are similar to its effects on ionotropic glutamate receptors. Asenapine also alters 2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)propionic acid (AMPA) and N-methyl-D-aspartic acid (NMDA) receptor binding without having demonstrable affinity for these receptors (Tarazi et al 2009). Given the diverse actions of cortical and hippocampal muscarinic receptor subtypes and the inability to specifically ascertain the receptor subtypes altered by asenapine in this study, the functional implications of these changes at the neuronal level require further investigation.…”

“…The modulation of these receptor systems by asenapine, together with effects on dopamine, serotonin, and ionotropic glutamate receptor subtypes (Tarazi et al 2008(Tarazi et al , 2009) may contribute to its efficacy in treating multiple symptom domains in patients with schizophrenia.…”

“…The asenapine doses selected are active in neurochemical and behavioural paradigms and were used for comparison with those studies (Franberg et al 2008;Tarazi et al 2008Tarazi et al , 2009. Gross motoric or weight effects are not observed with this treatment paradigm.…”

“…Preclinical studies have demonstrated that asenapine blocks the conditioned avoidance response (predictive of antipsychotic activity) without inducing catalepsy (predictive of extrapyramidal side-effects) (Franberg et al 2008). Repeated treatment with asenapine alters densities of dopamine, serotonin, and glutamate receptor subtypes in a fashion similar to that of second-but not first-generation antipsychotic drugs (Tarazi et al 2008(Tarazi et al , 2009.…”

Asenapine monotherapy in the acute treatment of both schizophrenia and bipolar&nbsp;I disorder

“…In contrast, in studies with monkeys, asenapine produced substantial improvement in executive functions which were maintained across a period of long-term dosing. 46 Further studies in rat brain have indicated that chronic treatment with asenapine exerts regional and dose-dependent effects on inotropic glutamate receptors, 47 thus another potential mechanism for its effectiveness in schizophrenia.…”