Kynurenic acid and schizophrenia.
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.
Erhardt
Sophie
S
Dept. of Physiology and Pharmacology, Karolinska Institutet, SE 171 77 Stockholm, Sweden. sophie.erhardt@fyfa.ki.se
Schwieler
Lilly
L
Engberg
Göran
G
D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism; D018698:Glutamic Acid / Q000172:deficiency; D006801:Humans; D007736:Kynurenic Acid / Q000378:metabolism*; D008297:Male; D008959:Models, Neurological; D010622:Phencyclidine / Q000633:toxicity; D011605:Psychoses, Substance-Induced / Q000209:etiology / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012559:Schizophrenia / Q000209:etiology* / Q000378:metabolism*; D017557:Ventral Tegmental Area / Q000187:drug effects / Q000378:metabolism
D014150:Antipsychotic Agents; D018698:Glutamic Acid; D007736:Kynurenic Acid; D010622:Phencyclidine; D004298:Dopamine