Long-term Effects of JL 13, a Potential Atypical Antipsychotic, on Ionotropic Glutamate Receptors

Abstract

Changes in ionotropic glutamate (Glu) N-methyl-d-aspartic acid (NMDA), and 2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)propionic acid (AMPA) receptors in rat forebrain regions were autoradiographically quantified after continuous infusion of JL 13 [(5-(4-methylpiperazin-1-yl)-8-chloro-pyrido[2,3-b][1,5]benzoxazepine fumarate] for 28 days using osmotic minipumps, and compared to the effects of representative typical (haloperidol) and atypical (clozapine, olanzapine, and risperidone) antipsychotic drugs from previous studies. Similar to other atypical and not typical antipsychotics, JL 13 decreased labeling of NMDA receptors in medial and lateral caudate-putamen (CPu; by 40%). These findings indicate that down-regulation of NMDA receptors by JL 13 and other atypical antipsychotic agents in CPu may contribute to their low risk of extrapyramidal side effects. In addition, and similar to olanzapine and risperidone, JL 13 increased AMPA receptor binding in CPu (by 42%). Changes in AMPA receptors may contribute to psychopharmacological properties of JL 13 and other atypical agents. Similar to clozapine, JL 13 did not alter levels of NMDA and AMPA receptors in hippocampus and entorhinal cortex. Long-term effects of JL 13 on ionotropic Glu receptors, as well as on other dopamine and serotonin receptors, support the atypical antipsychotic profile of this novel agent.

Asenapine exerts distinctive regional effects on ionotropic glutamate receptor subtypes in rat brain

“…As asenapine is likely to have modest D 2 receptor occupancy at doses below 0.03 mg/kg (Schotte et al, 1996), this suggests the effects on NMDA receptor binding density are likely to be mediated by the antiserotonergic properties of asenapine. These effects were similar to previously reported effects of the atypical antipsychotics clozapine, olanzapine, and risperidone, the experimental atypical antipsychotic JL13, but not the conventional agent haloperidol (Spurney et al, 1999;Tarazi et al, 1996Tarazi et al, , 2003Tarazi et al, , 2007.…”

“…Repeated treatment with asenapine significantly reduced NMDA receptor binding in rat medial and lateral CPu at doses associated with preferential antiserotonergic activity. These findings further indicate that decreases in NMDA receptors in the striatum may contribute to the relatively benign neurological profile observed with asenapine (Potkin et al, 2007), as well as currently available and experimental atypical antipsychotics (Baldessarini and Tarazi, 2005;Tarazi et al, 1999Tarazi et al, , 2003Tarazi et al, , 2007. Asenapine selectively decreased NMDA receptor levels in NAc, which may contribute to asenapine-induced increases in extracellular dopamine concentrations in the same brain region.…”

“…Nonspecific binding was determined by including 20 lM ketamine. After incubation, slices were washed in icecold 50 mM Tris-HCl buffer twice for 20 min and dried (Tarazi et al, 2003(Tarazi et al, , 2007.…”

“…Nonspecific binding was determined with 30 lM unlabeled CNQX. After incubation, slices were washed in the ice-cold Tris buffer three times for 10 s and dried (Tarazi et al, 2007).…”

“…1) and quantified using a computerized densitometric image analyzer (MCID-M4; Imaging Research, St. Catharines, ON, Canada). The calibrated [ 3 H]standards were used to convert optical density to nCi/mg of tissue, and specific (total minus nonspecific) binding was expressed as fmol/mg tissue (Tarazi et al, 2003(Tarazi et al, , 2007.…”