title: Differential effects of AMPA receptor potentiators and glycine reuptake inhibitors on antipsychotic efficacy and prefrontal glutamatergic transmission.
abstract: BACKGROUND
  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.
  
  
  OBJECTIVE
  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: Department of Physiology and Pharmacology, The Karolinska Institutet, Stockholm, Sweden. Kent.Jardemark@ki.se
authors: Kent
authors: K
authors: Jardemark
authors: Monica M
authors: MM
authors: Marcus
authors: Anna
authors: A
authors: Malmerfelt
authors: Mohammed
authors: M
authors: Shahid
authors: Torgny H
authors: TH
authors: Svensson
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000819:agonists* / Q000494:pharmacology; D001362:Avoidance Learning / Q000187:drug effects / Q000502:physiology*; D001569:Benzodiazepines / Q000819:agonists / Q000494:pharmacology; D002375:Catalepsy / Q000503:physiopathology; D004357:Drug Synergism; D018698:Glutamic Acid / Q000378:metabolism*; D050487:Glycine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors; D006220:Haloperidol / Q000819:agonists / Q000494:pharmacology; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D000077152:Olanzapine; D010069:Oxadiazoles / Q000008:administration & dosage / Q000494:pharmacology*; D010880:Piperidines / Q000008:administration & dosage / Q000494:pharmacology*; D017397:Prefrontal Cortex / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D018091:Receptors, AMPA / Q000819:agonists*; D018967:Risperidone / Q000819:agonists / Q000494:pharmacology*; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*; D013764:Tetrahydronaphthalenes / Q000494:pharmacology; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: C521407:1-(benzofurazan-5-ylcarbonyl)piperidine; D014150:Antipsychotic Agents; D050487:Glycine Plasma Membrane Transport Proteins; C520612:N-methyl-N-(6-methoxy-1-phenyl-1,2,3,4-tetrahydronaphthalen-2-ylmethyl)aminomethylcarboxylic acid; C545643:Org 26576; D010069:Oxadiazoles; D010880:Piperidines; D018091:Receptors, AMPA; D013764:Tetrahydronaphthalenes; D001569:Benzodiazepines; D018698:Glutamic Acid; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D006220:Haloperidol; D018967:Risperidone; D000077152:Olanzapine