Long-term exposure to nicotine markedly reduces kynurenic acid in rat brain--in vitro and ex vivo evidence.
Kynurenic acid (KYNA) is a recognized broad-spectrum antagonist of excitatory amino acid receptors with a particularly high affinity for the glycine co-agonist site of the N-methyl-D-aspartate (NMDA) receptor complex. KYNA is also a putative endogenous neuroprotectant. Recent studies show that KYNA strongly blocks alpha7 subtype of nicotinic acetylcholine receptors (nAChRs). The present studies were aimed at assessing effects of acute and chronic nicotine exposure on KYNA production in rat brain slices in vitro and ex vivo. In brain slices, nicotine significantly increased KYNA formation at 10 mM but not at 1 or 5 mM. Different nAChR antagonists (dihydro-beta-erythroidine, methyllycaconitine and mecamylamine) failed to block the influence exerted by nicotine on KYNA synthesis in cortical slices in vitro. Effects of acute (1 mg/kg, i.p.), subchronic (10-day) and chronic (30-day) administration of nicotine in drinking water (100 microg/ml) on KYNA brain content were evaluated ex vivo. Acute treatment with nicotine (1 mg/kg i.p.) did not affect KYNA level in rat brain. The subchronic exposure to nicotine in drinking water significantly increased KYNA by 43%, while chronic exposure to nicotine resulted in a reduction in KYNA by 47%. Co-administration of mecamylamine with nicotine in drinking water for 30 days reversed the effect exerted by nicotine on KYNA concentration in the cerebral cortex. The present results provide evidence for the hypothesis of reciprocal interaction between the nicotinic cholinergic system and the kynurenine pathway in the brain.
Zielińska
Elzbieta
E
Department of Toxicology, Institute of Agricultural Medicine, Jaczewskiego 2, 20-950 Lublin, Poland.
Kuc
Damian
D
Zgrajka
Wojciech
W
Turski
Waldemar A
WA
Dekundy
Andrzej
A
D000284:Administration, Oral; D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004334:Drug Administration Schedule; D007274:Injections, Intraperitoneal; D007736:Kynurenic Acid / Q000097:blood / Q000378:metabolism*; D008297:Male; D009538:Nicotine / Q000008:administration & dosage / Q000633:toxicity*; D018722:Nicotinic Agonists / Q000008:administration & dosage / Q000633:toxicity*; D018733:Nicotinic Antagonists / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D011978:Receptors, Nicotinic / Q000187:drug effects* / Q000378:metabolism; D000637:Transaminases / Q000378:metabolism
D018722:Nicotinic Agonists; D018733:Nicotinic Antagonists; D011978:Receptors, Nicotinic; D009538:Nicotine; D000637:Transaminases; C021481:kynurenine-oxoglutarate transaminase; D007736:Kynurenic Acid