A Glycine Site Associated with N‐Methyl‐<scp>d</scp>‐Aspartic Acid Receptors: Characterization and Identification of a New Class of Antagonists

127

Brain levels of kynurenic acid (KYNA), an endogenous antagonist of glycine B /NMDA and a-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.

Section: Discussionmentioning

confidence: 99%

Micromolar Brain Levels of Kynurenic Acid are Associated with a Disruption of Auditory Sensory Gating in the Rat

Shepard

Joy

Clerkin

et al. 2003

127

“…KYNA is a noncompetitive antagonist of the NMDA receptor ion-channel complex, acting on the strychnine-insensitive glycine recognition site (Birch et al, 1988), with an IC 50 in the low micromolar range (IC 50 ¼ 7.9 mM; Ganong and Cotman, 1986;Kessler et al, 1989;Parsons et al, 1997). Furthermore, a recent study showed that KYNA blocks the a7* nicotinic receptor with the same IC 50 value as for the glycine-site of the NMDA receptors (Hilmas et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

Inhibitory Action of Clozapine on Rat Ventral Tegmental Area Dopamine Neurons Following Increased Levels of Endogenous Kynurenic Acid

Schwieler

Erhardt

2003

The mode of action by which the atypical antipsychotic drug clozapine exerts its superior efficacy to ameliorate both positive and negative symptoms is still unknown. In the present in vivo electrophysiological study, we investigate the effects of haloperidol (a typical antipsychotic drug) and clozapine on ventral tegmental area (VTA) dopamine (DA) neurons in a situation of hyperdopaminergic activity in order to mimic tentatively a condition similar to that seen in schizophrenia. Increased DA transmission was induced by elevating endogenous levels of the N-methyl-D-aspartate receptor and a7* nicotinic receptor antagonist kynurenic acid (KYNA; by means of PNU 156561A, 40 mg /kg, i.v.). In control rats, i.v. administered haloperidol (0.05-0.8 mg/kg) or clozapine (1.25-10 mg/kg) was associated with increased firing rate and burst firing activity of VTA DA neurons. However, in rats displaying hyperdopaminergia (induced by elevated levels of KYNA), the effects of clozapine on VTA DA neurons were converted into pure inhibitory responses, including decrease in burst firing activity. In contrast, haloperidol still produced an excitatory action on VTA DA neurons in rats with elevated levels of endogenous brain KYNA. The results of the present study suggest that clozapine facilitates or inhibits VTA DA neurotransmission, depending on brain concentration of KYNA. Such an effect of clozapine may be related to its unique effect in also ameliorating negative symptoms of schizophrenia.

“…Consequently, intracerebral application of large amounts of KYNA has long been known to exert neuroprotective and anticonvulsant effects in experimental animals (Foster et al, 1984). At much lower concentrations, KYNA inhibits the strychnine-insensitive glycine coagonist site of the NMDA receptor (IC 50 : 8mM; Kessler et al, 1989), and recent evidence favors a physiological action of KYNA as an Animals were killed 1 h after the final injection of nicotine (1 mg/kg, s.c., b.i.d. ), and the blood was processed as described in the text.…”

Section: Discussionmentioning

confidence: 99%

“…KYNA, long known as an antagonist of the glycine coagonist site of the NMDA receptor (Kessler et al, 1989), blocks a7 nAChR activity at even lower, endogenous brain concentrations (Hilmas et al, 2001), and reductions in brain KYNA levels were recently found to increase a7 nAChR function (Alkondon et al, 2004). It is therefore conceivable that nicotine-induced fluctuations in brain KYNA levels influence the activity of a7 nAChRs (Hilmas et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

Prolonged Nicotine Administration Results in Biphasic, Brain-Specific Changes in Kynurenate Levels in the Rat

Rassoulpour

Albuquerque

et al. 2004

The content of the endogenous NMDA and a7 nicotinic acetylcholine receptor antagonist kynurenate (KYNA) is increased in the cerebral cortex and cerebrospinal fluid of patients with schizophrenia. In view of the very high incidence of smoking in schizophrenic individuals, a study was designed to examine the effect of acute and prolonged nicotine administration on brain KYNA levels in experimental animals. Adult male rats received subcutaneous nicotine injections twice daily for up to 10 days, and animals were routinely killed 1 h after the last injection. Neither acute treatment nor a 2-day regimen with 1 mg/kg nicotine ( ¼ 0.35 mg/kg pure base) caused changes in cerebral KYNA levels. Four-or 6 day-treatment with this dose resulted in 20-40% decreases in cerebral KYNA content. Animals treated with 1 or 10 mg/kg nicotine for 10 days showed dose-dependent, significant increases in KYNA in hippocampus, striatum, and cortex, but not in the serum. Discontinuation of nicotine treatment for 7 days restored brain KYNA to control levels. Separate animals, implanted with osmotic minipumps delivering 2 mg/kg of nicotine/day for 10 days also showed significant elevations in brain KYNA. Hippocampal microdialysis, performed in animals receiving nicotine (1 mg/kg) for 10 days, revealed a significant increase in basal extracellular KYNA levels compared to controls, whereas acute treatment with this dose produced no such change. Measurements of KYNA's bioprecursor kynurenine in brain or blood did not reveal any nicotine-induced changes. These results indicate that nicotine has a brain-specific, biphasic effect on the transamination of kynurenine to KYNA. Such nicotine-induced fluctuations in brain KYNA may cause functional changes in processes that regulate glutamatergic and cholinergic neurotransmission in the normal and diseased brain.