Endogenous kynurenic acid disrupts prepulse inhibition.
BACKGROUND
Recent studies show that endogenous levels of kynurenic acid (KYNA) are increased in the cerebrospinal fluid of schizophrenic patients. Prepulse inhibition (PPI) of the acoustic startle reflex is an operational measure of sensorimotor gating that is reduced in neuropsychiatric disorders, such as schizophrenia. Previous studies show that administration of N-methyl-D-aspartate (NMDA) receptor antagonists, such as phencyclidine or MK-801, leads to deficits in sensorimotor gating that mimic those observed in schizophrenic patients.


METHODS
The present study examined the effects of the endogenous NMDA receptor antagonist KYNA on startle and PPI in rats. Elevation of endogenous brain levels of KYNA was achieved through intraperitoneal (IP) administration of kynurenine (100 mg/kg), the precursor of KYNA, or by intravenous administration of PNU 156561A (10 mg/kg).


RESULTS
A fourfold increase in brain KYNA levels, as induced by kynurenine or PNU 156561A, significantly reduced PPI. There were no differences in startle magnitudes between control rats and drug-treated rats. The disruption of PPI was restored by administration of the antipsychotic drugs haloperidol (.2 mg/kg, IP) or clozapine (7.5 mg/kg, IP).


CONCLUSIONS
The present results suggest that brain KYNA serves as an endogenous modulator of PPI and are consistent with the hypothesis that KYNA contributes to the pathophysiology of schizophrenia.
Department of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden. Sophie.Erhardt@fyfa.ki.se
Sophie
S
Erhardt
Lilly
L
Schwieler
Carolina
C
Emanuelsson
Mark
M
Geyer
D000161:Acoustic Stimulation / Q000379:methods; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology; D001921:Brain / Q000187:drug effects / Q000378:metabolism* / Q000528:radiation effects; D001923:Brain Chemistry / Q000187:drug effects; D002087:Butyrates / Q000494:pharmacology; D003024:Clozapine / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000494:pharmacology; D004307:Dose-Response Relationship, Radiation; D004347:Drug Interactions; D006220:Haloperidol / Q000494:pharmacology; D007736:Kynurenic Acid / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007737:Kynurenine / Q000494:pharmacology; D008297:Male; D009433:Neural Inhibition / Q000187:drug effects* / Q000502:physiology; D011339:Probenecid / Q000494:pharmacology; D051381:Rats; D013216:Reflex, Startle / Q000187:drug effects*
D014150:Antipsychotic Agents; D002087:Butyrates; D018492:Dopamine Antagonists; C104254:FCE 28833; D007737:Kynurenine; D007736:Kynurenic Acid; D003024:Clozapine; D006220:Haloperidol; D011339:Probenecid