Kynurenic acid and schizophrenia.

Schizophrenia may involve a glutamate deficiency, with the endogenous glutamate antagonist kynurenic acid (KYNA) playing a role. In anesthetized rats, pharmacologically elevated KYNA increased firing and burst activity of midbrain dopamine neurons, similar to effects of psychotomimetics PCP and ketamine. Cerebrospinal fluid KYNA was higher in 28 male first-episode schizophrenia patients (1.67 ± 0.27 nM) than in 17 male healthy controls (0.97 ± 0.07 nM). Elevated KYNA also reversed clozapine's excitatory effect on rat dopamine neurons to inhibition. The study suggests KYNA contributes to schizophrenia pathogenesis, linking dopamine and glutamate hypotheses.

Study at a glance

Abstract

In recent years the "dopamine (DA) hypothesis of schizophrenia", has been modified into a more diversified view where an attenuated glutamatergic neurotransmission is believed to participate in the pathogenesis of the disease. Thus, schizophrenia may be regarded as a glutamate deficiency disorder. Kynurenic acid (KYNA) is an endogenous glutamate antagonist with a preferential action at the glycinesite of the N-methyl D-aspartate (NMDA)-receptor. Mounting evidence indicates that the compound is significantly involved in basal neurophysiological processes in the brain. Thus, in anaesthetized rats, pharmacologically elevated KYNA concentration (by means of PNU 156561A) was associated with increased firing rate and burst firing activity of midbrain DA neurons. Similar alterations in basal firing characteristics are also observed following systemic administration of PCP or ketamine, indicating per se that elevated levels of brain KYNA is associated with psychotomimetic effects. Indeed, cerebrospinal fluid (CSF) level of kynurenic acid was elevated in 28 male first episode schizophrenic patients (1.67 +/- 0.27 nM) as compared to 17 male healthy controls (0.97 +/- 0.07 nM. Elevated brain KYNA concentration was also found to dramatically affect the responsivity of rat midbrain DA neurons to the atypical antipsychotic drug clozapine. Thus, whereas clozapine produced increased firing rate and burst firing activity of these neurons in untreated rats, elevation of brain KYNA levels was found to reverse the action of clozapine into a pure inhibitory response. The present study suggests a contribution of KYNA in the pathogenesis of schizophrenia and link the dopamine hypothesis of schizophrenia together with the idea of a deficiency of glutamate function in this disease.