Differential effects of AMPA receptor potentiators and glycine reuptake inhibitors on antipsychotic efficacy and prefrontal glutamatergic transmission.

Abstract

RATIONALE:

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.

OBJECTIVES:

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.

METHODS:

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.

RESULTS:

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.

CONCLUSIONS:

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.

• Authors: Kent Jardemark, Monica M Marcus, Anna Malmerfelt, Mohammed Shahid, Torgny H Svensson
• Journal: Psychopharmacology (Psychopharmacology (Berl)) Vol. 221 Issue 1 Pg. 115-31 (May 2012) ISSN: 1432-2072 [Electronic] Germany
• PMID: 22068461 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 1-(benzofurazan-5-ylcarbonyl)piperidine
• Antipsychotic Agents
• Glycine Plasma Membrane Transport Proteins
• N-methyl-N-(6-methoxy-1-phenyl-1,2,3,4-tetrahydronaphthalen-2-ylmethyl)aminomethylcarboxylic acid
• Org 26576
• Oxadiazoles
• Piperidines
• Receptors, AMPA
• Tetrahydronaphthalenes
• Benzodiazepines
• Glutamic Acid
• alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
• Haloperidol
• Risperidone
• Olanzapine

Topics

• Animals
• Antipsychotic Agents (agonists, pharmacology)
• Avoidance Learning (drug effects, physiology)
• Benzodiazepines (agonists, pharmacology)
• Catalepsy (physiopathology)
• Drug Synergism
• Glutamic Acid (metabolism)
• Glycine Plasma Membrane Transport Proteins (antagonists & inhibitors)
• Haloperidol (agonists, pharmacology)
• Male
• Membrane Potentials (drug effects, physiology)
• Olanzapine
• Oxadiazoles (administration & dosage, pharmacology)
• Piperidines (administration & dosage, pharmacology)
• Prefrontal Cortex (drug effects, physiology)
• Rats
• Rats, Wistar
• Receptors, AMPA (agonists)
• Risperidone (agonists, pharmacology)
• Synaptic Transmission (drug effects, physiology)
• Tetrahydronaphthalenes (pharmacology)
• alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (administration & dosage, analogs & derivatives, pharmacology)