Kynurenine 3-mono-oxygenase inhibitors reduce glutamate concentration in the extracellular spaces of the basal ganglia but not in those of the cortex or hippocampus.
Kynurenine 3-mono-oxygenase (KMO, kynurenine hydroxylase) inhibitors increase brain kynurenic acid (KYNA) synthesis and cause pharmacological actions possibly mediated by a reduced activity of excitatory synapses. We used in vivo microdialysis and passive avoidance to study the effects of local KYNA or systemic KMO inhibitor administration on glutamate (GLU) neurotransmission. Local application of KYNA (30-100 nM) through reverse microdialysis reduced GLU content in caudate and cortical dialysates by 75 and 55%, respectively. No changes were found in the hippocampus. Systemic administration of Ro 61-8048 (4-40 mg/kg) increased KYNA levels in dialysates obtained from the cortex (from 10.3 +/- 1.9 to 45.5 +/- 15 nM), caudate (from 2.4 +/- 0.8 to 9.5 +/- 0.9 nM) and hippocampus (from 7.7 +/- 1.7 to 19.2 +/- 3.5 nM). It also caused a parallel robust decrease in GLU levels in the dialysates collected from the caudate (from 2.2 +/- 0.5 to 0.63 +/- 0.05 microM) but not in those collected from the parietal cortex or the hippocampus. In a passive avoidance paradigm, the administration of the NMDA receptor antagonist MK-801 (0.1 mg/kg) reduced, while Ro 61-8048 (4-80 mg/kg) did not change the latency time of entering into the dark compartment on the recall trial. Our data show that KMO inhibitors increase brain KYNA synthesis and selectively reduce GLU extracellular concentration in the basal ganglia.
Moroni
F
F
Department of Pharmacology, University of Florence, Viale Pieraccini 6, 50134 Firenze, Italy. flavio.moroni@unifi.it
Cozzi
A
A
Carpendo
R
R
Cipriani
G
G
Veneroni
O
O
Izzo
E
E
D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects; D001479:Basal Ganglia / Q000187:drug effects* / Q000378:metabolism; D001522:Behavior, Animal / Q000187:drug effects; D001923:Brain Chemistry / Q000187:drug effects*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005110:Extracellular Space / Q000187:drug effects* / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism*; D007736:Kynurenic Acid / Q000378:metabolism / Q000494:pharmacology; D050601:Kynurenine 3-Monooxygenase; D008297:Male; D017551:Microdialysis / Q000379:methods; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors*; D011189:Potassium Chloride / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D018709:Statistics, Nonparametric; D013449:Sulfonamides / Q000494:pharmacology*; D013844:Thiazoles / Q000494:pharmacology*; D013997:Time Factors; D020866:omega-Conotoxin GVIA / Q000494:pharmacology
D002121:Calcium Channel Blockers; C110196:Ro 61-8048; D013449:Sulfonamides; D013844:Thiazoles; D018698:Glutamic Acid; D011189:Potassium Chloride; D020866:omega-Conotoxin GVIA; D006899:Mixed Function Oxygenases; D050601:Kynurenine 3-Monooxygenase; D007736:Kynurenic Acid