Activation of rat ventral tegmental area dopamine neurons by endogenous kynurenic acid: a pharmacological analysis.
Kynurenic acid (KYNA) is an endogenous NMDA receptor antagonist as well as a blocker of the alpha7* nicotinic receptor and mounting evidence suggests that the compound participates in the pathophysiology of schizophrenia. Previous studies have shown that elevated levels of endogenous KYNA are associated with an increased firing of midbrain dopamine (DA) neurons. In the present study, utilizing extracellular single unit cell recording techniques, the mechanism involved in this excitatory action of the compound was analyzed in male Sprague-Dawley rats. Administration of 4-chlorokynurenine (4-Cl-KYN; 25mg/kg, i.p.), which is converted to the selective NMDA glycine-site antagonist 7-chloro-kynurenic acid (7-Cl-KYNA), was found to increase firing rate and per cent burst firing activity of ventral tegmental area (VTA) DA neurons to the same magnitude as pretreatment of kynurenine (causing a 25-fold elevation in extracellular brain KYNA). Intravenous administration of the selective antagonist at the alpha7* nicotinic receptor methyllycaconitine (MLA; 1-4mg/kg) did not affect firing of VTA DA neurons, whereas intraperitoneal administration of this drug in a high dose (6mg/kg) was associated with a decreased firing rate and per cent burst firing activity. Administration of SDZ 220-581 (10mg/kg, i.v.), a competitive antagonist at the glutamate recognition-site of the NMDA receptor, was found to increase firing rate and per cent burst firing. Present results have potential implications for the treatment of schizophrenia, and indicate that the increased activity of VTA DA neurons following elevation of brain KYNA is mediated through glutamatergic rather than by nicotinergic mechanisms.
Linderholm
Klas R
KR
Department of Physiology and Pharmacology, Karolinska Institutet, 171 77 Stockholm, Sweden.
Andersson
Alexandra
A
Olsson
Sara
S
Olsson
Elin
E
Snodgrass
Ralph
R
Engberg
Göran
G
Erhardt
Sophie
S
D000157:Aconitine / Q000031:analogs & derivatives / Q000494:pharmacology; D000200:Action Potentials / Q000187:drug effects; D000704:Analysis of Variance; D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D007736:Kynurenic Acid / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D017551:Microdialysis; D009474:Neurons / Q000187:drug effects*; D018733:Nicotinic Antagonists / Q000494:pharmacology; D011422:Propionates / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D018709:Statistics, Nonparametric; D013997:Time Factors; D017557:Ventral Tegmental Area / Q000166:cytology*
D001713:Biphenyl Compounds; D018691:Excitatory Amino Acid Antagonists; D018733:Nicotinic Antagonists; D011422:Propionates; D016194:Receptors, N-Methyl-D-Aspartate; C104918:alpha-amino-2'-chloro-5-(phosphonomethyl)(1,1'-biphenyl)-3-propanoic acid; C054634:methyllycaconitine; D007736:Kynurenic Acid; C057013:7-chlorokynurenic acid; D004298:Dopamine; D000157:Aconitine