Effects of the selective kainate receptor antagonist ACET on altered sensorimotor gating in a genetic model of reduced NMDA receptor function.
The pathophysiology of schizophrenia may involve reduced NMDA receptor function. Accordingly, experimental models of NMDA receptor hypofunction may be useful for testing potential new antipsychotic agents and for characterizing neurobiological abnormalities relevant to schizophrenia. We demonstrated previously that mice under-expressing the NR1 subunit of the NMDA receptor show supersensitive behavioral responses to kainic acid and that a kainate receptor antagonist normalized altered behaviors in the mutant mice (NR1(neo/neo)). The present work examined effects of another selective kainate receptor antagonist, (S)-1-(2-Amino-2-carboxyethyl)-3-(2-carboxy-5-phenylthiophene-3-yl-methylpyrimidine-2,4-dione (ACET), on altered behavioral phenotypes in the genetic model of NMDA receptor hypofunction. ACET, at a dose of 15 mg/kg, partially reversed the deficits in prepulse inhibition produced by the mutation. The 15 mg/kg dose of ACET was also effective in reversing behavioral effects of the selective kainate agonist ATPA. However, ACET did not significantly reduce the increased locomotor activity and rearing behavior observed in the NR1(neo/neo) mice. These findings show that a highly selective kainate receptor antagonist can affect the deficits in sensorimotor gating in the NR1(neo/neo) mice. The results also provide further support for the idea that selective kainate receptor antagonists could be novel therapeutic candidates for schizophrenia.
Department of Psychiatry, University of North Carolina at Chapel Hill, NC 27599, USA. gduncan@med.unc.edu
Gary E
GE
Duncan
Beverly H
BH
Koller
Sheryl S
SS
Moy
D000409:Alanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D002352:Carrier Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D055785:Gene Knockdown Techniques; D007555:Isoxazoles / Q000494:pharmacology*; D051379:Mice; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011422:Propionates / Q000494:pharmacology*; D018092:Kainic Acid Receptors / Q000819:agonists; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D012559:Schizophrenia / Q000188:drug therapy* / Q000503:physiopathology; D014498:Uracil / Q000031:analogs & derivatives* / Q000494:pharmacology
D000409:Alanine; D014150:Antipsychotic Agents; D002352:Carrier Proteins; D007555:Isoxazoles; D009419:Nerve Tissue Proteins; D011422:Propionates; D018092:Kainic Acid Receptors; D016194:Receptors, N-Methyl-D-Aspartate; D014498:Uracil; C519517:1-(2-amino-2-carboxyethyl)-3-(2-carboxy-5-phenylthiophene-3-ylmethyl)-5-methylpyrimidine-2,4-dione; C121673:Gprin1 protein, mouse; C081662:alpha-amino-3-hydroxy-5-tert-butyl-4-isoxazolepropionate