Elevated levels of kynurenic acid change the dopaminergic response to amphetamine: implications for schizophrenia.
Kynurenic acid (KYNA) is an endogenous compound implicated in the pathophysiology of schizophrenia. This tryptophan metabolite antagonizes both the N-methyl-D-aspartate (NMDA) receptors and the nicotinic alpha7* receptors at micromolar concentrations. In the present study the effects of amphetamine on dopamine (DA) release in the nucleus accumbens and on firing of DA neurons in the ventral tegmental area (VTA) were investigated in rats treated with kynurenine, the precursor of KYNA, in order to elevate brain KYNA levels. In rats subchronically treated with kynurenine (90 mg/kg x d for 6 d via osmotic minipumps, resulting in a 2-fold increase in whole-brain KYNA), the amphetamine-induced (2 mg/kg i.p.) increase in accumbal DA release was clearly enhanced compared to controls. Furthermore, subchronic treatment with kynurenine reduced the inhibitory action of amphetamine (0.2-25.6 mg/kg i.v.) on firing rate and burst firing activity of VTA DA neurons. A single dose of kynurenine (5 mg/kg s.c., 60 min, resulting in a 3-fold increase in whole-brain KYNA) did not alter the amphetamine-induced effects on DA neurotransmission compared to control rats. Present data are in agreement with the increased striatal DA release by amphetamine as observed by brain-imaging studies in patients with schizophrenia. Thus, subchronic elevation of rat brain KYNA, may rationally serve as an animal model similar to a pathophysiological condition of schizophrenia. It is proposed that the reduced responsivity of VTA DA neurons to the inhibitory action of amphetamine observed in rats with subchronically elevated KYNA levels may partly account for the increase in terminal DA release.
Olsson
Sara K
SK
Department of Physiology & Pharmacology, Karolinska Institutet, Stockholm, Sweden.
Andersson
Alexandra S
AS
Linderholm
Klas R
KR
Holtze
Maria
M
Nilsson-Todd
Linda K
LK
Schwieler
Lilly
L
Olsson
Elin
E
Larsson
Kerstin
K
Engberg
Göran
G
Erhardt
Sophie
S
D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects; D003627:Data Interpretation, Statistical; D003913:Dextroamphetamine / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism / Q000502:physiology*; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004343:Drug Implants; D004594:Electrophysiology; D018691:Excitatory Amino Acid Antagonists / Q000097:blood / Q000378:metabolism / Q000494:pharmacology*; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism; D007736:Kynurenic Acid / Q000097:blood / Q000378:metabolism / Q000494:pharmacology*; D007737:Kynurenine / Q000494:pharmacology; D008297:Male; D017551:Microdialysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D012559:Schizophrenia / Q000188:drug therapy*
D018765:Dopamine Uptake Inhibitors; D004343:Drug Implants; D018691:Excitatory Amino Acid Antagonists; D007737:Kynurenine; D007736:Kynurenic Acid; D003913:Dextroamphetamine; D004298:Dopamine