Increased phasic activity of dopaminergic neurones in the rat ventral tegmental area following pharmacologically elevated levels of endogenous kynurenic acid.
Kynurenic acid (KYNA) is an antagonist of ionotropic glutamate receptors, preferentially blocking the glycine-site of the N-methyl-D-aspartate (NMDA) receptor. In the present electrophysiological study, the firing pattern of dopamine (DA) neurones of rat ventral tegmental area (VTA) was investigated following pharmacologically elevated endogenous levels of KYNA by means of an inhibitor of kynurenine 3-hydroxylase (PNU 156561A). Pre-treatment with PNU 156561A (40 mg kg-1, i.v., 5-9 h) caused a threefold increase in endogenous KYNA in whole brain levels and also evoked a significant increase in firing rate and bursting activity of VTA DA neurones. Administration of D-cycloserine (2-128 mg kg-1, i.v.), a partial agonist at the glycine-site of the NMDA-receptor, was found to reverse the increase in firing rate and bursting activity as induced by elevated concentrations of KYNA. The electrophysiological effects of elevated KYNA levels were in all essential mimicked by administration of the NMDA-receptor antagonist MK 801 (0.05-1.6 mg kg-1, i.v.). Thus, the effects of elevated endogenous brain KYNA observed in the present study are likely to be carried out by NMDA receptor antagonism. In conclusion, this study shows that an increase in endogenous KYNA levels produces significant actions on the tonic afferent control of the firing pattern of VTA DA neurones. Given the psychotomimetic effects of NMDA-receptor antagonists, e.g. phencyclidine and ketamine, the state of hyperactivity of mesocorticolimbic DA system induced by elevated levels of KYNA may represent a pathophysiological condition analogous to that seen in schizophrenic patients.
Erhardt
S
S
Department of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden.
Engberg
G
G
D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D000963:Antimetabolites / Q000494:pharmacology; D002087:Butyrates / Q000494:pharmacology; D003523:Cycloserine / Q000494:pharmacology; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004298:Dopamine / Q000502:physiology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D007736:Kynurenic Acid / Q000378:metabolism*; D008297:Male; D009474:Neurons / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012559:Schizophrenia / Q000378:metabolism / Q000503:physiopathology; D017557:Ventral Tegmental Area / Q000166:cytology / Q000502:physiology*
D000963:Antimetabolites; D002087:Butyrates; D018691:Excitatory Amino Acid Antagonists; C104254:FCE 28833; D016291:Dizocilpine Maleate; D003523:Cycloserine; D007736:Kynurenic Acid; D004298:Dopamine