title: Micromolar brain levels of kynurenic acid are associated with a disruption of auditory sensory gating in the rat.
abstract: Brain levels of kynurenic acid (KYNA), an endogenous antagonist of glycine(B)/NMDA and alpha-7 nicotinic acetylcholine receptors, are elevated in individuals with schizophrenia. Both receptors are broadly implicated in the pathophysiology of this disease, particularly in the deficits many patients show in filtering the sensorium. In the present study, we sought to determine whether elevated brain levels of KYNA disrupt auditory gating in anesthetized rats. A mid-latency evoked potential was recorded from the hippocampus in response to a pair of auditory tones. Gating was assessed by determining the ratio of the amplitude of test and conditioning responses (T/C ratio) in rats that had received KYNA's precursor L-kynurenine (KYN; 150 mg/kg, i.p.) together with probenecid (PBCD; 200 mg/kg, i.p.) 2 h prior to the start of the recording session. KYNA levels in the hippocampus of KYN+PBCD-treated rats were increased 500-fold, and accompanied by a significant increase in T/C ratio consistent with a disruption in sensory gating. PBCD alone increased hippocampal KYNA 12-fold, but did not significantly elevate T/C ratio. L-701,324 (3-30 mg/kg, i.v.), a centrally acting glycine(B) site antagonist, also failed to disrupt gating; however, large quantities of the competitive NMDA receptor antagonist DL-2-amino-5-phosphopentanoate (200 nmol, i.c.v.) markedly increased T/C ratio. Thus, while total blockade of NMDA receptors disrupts auditory gating, partial blockade achieved by antagonism of its glycine coagonist binding site does not. These observations indicate that the disruption in auditory processing in rats with greatly elevated KYNA levels is not attributable to the compound's antagonist actions at the glycine(B) receptor.
authors.affiliation: Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, PO Box 21247, Baltimore, MD 21228, USA. pshepard@mprc.umaryland.edu
authors.forename: Paul D
authors.initials: PD
authors.lastname: Shepard
authors.forename: Brian
authors.initials: B
authors.lastname: Joy
authors.forename: Lucy
authors.initials: L
authors.lastname: Clerkin
authors.forename: Robert
authors.initials: R
authors.lastname: Schwarcz
mesh_terms: D000161:Acoustic Stimulation / Q000379:methods*; D000818:Animals; D001921:Brain / Q000378:metabolism*; D005072:Evoked Potentials, Auditory / Q000502:physiology*; D007736:Kynurenic Acid / Q000378:metabolism*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D018009:Receptors, Glycine / Q000037:antagonists & inhibitors / Q000502:physiology
chemical_list: C491948:Glrb protein, rat; D018009:Receptors, Glycine; D007736:Kynurenic Acid