Differential effects of AMPA receptor potentiators and glycine reuptake inhibitors on antipsychotic efficacy and prefrontal glutamatergic transmission
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The α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor positive allosteric modulators (AMPA-PAMs), Org 24448 and Org 26576, and the glycine transporter-1 (GlyT-1) inhibitor Org 25935 are developed for treatment of schizophrenia.
Here we examined experimentally the ability of co-administration of these AMPA-PAMs or the GlyT-1 inhibitor to augment the antipsychotic activity and effect on cortical N-methyl-d-aspartate (NMDA) receptor-mediated transmission of risperidone, olanzapine, or haloperidol.
We examined antipsychotic efficacy using the conditioned avoidance response (CAR) test, extrapyramidal side effect liability using a catalepsy test, and cortical NMDA receptor-mediated glutamatergic transmission using intracellular electrophysiological recording technique in vitro.
Both AMPA-PAMs enhanced the suppression of CAR induced by risperidone or olanzapine, and Org 24448 also enhanced the effect of haloperidol. In contrast, the GlyT-1 inhibitor did not cause any behaviorally significant effect in the CAR test. However, the GlyT-1 inhibitor, but not the AMPA-PAMs, produced a large facilitation of NMDA-induced currents. All three drugs potentiated the effect of risperidone but not haloperidol on these currents. The GlyT-1 inhibitor also facilitated the effect of olanzapine. All drugs potentiated the effect of risperidone on electrically stimulated excitatory postsynaptic potentials (EPSP) in cortical pyramidal cells, whereas only the GlyT inhibitor facilitated the effect of olanzapine.
Our results suggest that the AMPA-PAMs, when compared to the GlyT-1 inhibitor, show differential effects in terms of augmentation of antipsychotic efficacy, particularly when combined with risperidone or olanzapine. Both AMPA-PAMs and the GlyT-1 inhibitor may also improve negative symptoms and cognitive impairments in schizophrenia, in particular when combined with risperidone.
KeywordsAMPA receptor potentiators GlyT1 inhibitor Org 24448 Org 26576 Org 25935 Schizophrenia Antipsychotic
This work was supported by the Swedish Research Council grant nos. 4747 and 15049, the Karolinska Institutet, and a research grant from Department of Molecular Pharmacology, MSD, Newhouse, UK.
Conflict of interest
Apart from the grant received from MSD, there is no conflict of interest. Kent Jardemark is employee at the Karolinska Institutet and Chalmers University of Technology. Torgny H. Svensson, Monica M. Marcus, and Anna Malmerfelt are employees at the Karolinska Institutet, and Mohammed Shahid is a previous employee at Department of Molecular Pharmacology, MSD, Newhouse, UK. All experiments were approved by and conducted in accordance with the local Animal Ethics Committee, Stockholm North and the Karolinska Institutet, Sweden.
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