Prolonged Nicotine Administration Results in Biphasic, Brain-Specific Changes in Kynurenate Levels in the Rat

Abstract

The content of the endogenous NMDA and alpha7 nicotinic acetylcholine receptor antagonist kynurenate (KYNA) is increased in the cerebral cortex and cerebrospinal fluid of patients with schizophrenia. In view of the very high incidence of smoking in schizophrenic individuals, a study was designed to examine the effect of acute and prolonged nicotine administration on brain KYNA levels in experimental animals. Adult male rats received subcutaneous nicotine injections twice daily for up to 10 days, and animals were routinely killed 1 h after the last injection. Neither acute treatment nor a 2-day regimen with 1 mg/kg nicotine (= 0.35 mg/kg pure base) caused changes in cerebral KYNA levels. Four- or 6 day-treatment with this dose resulted in 20-40% decreases in cerebral KYNA content. Animals treated with 1 or 10 mg/kg nicotine for 10 days showed dose-dependent, significant increases in KYNA in hippocampus, striatum, and cortex, but not in the serum. Discontinuation of nicotine treatment for 7 days restored brain KYNA to control levels. Separate animals, implanted with osmotic minipumps delivering 2 mg/kg of nicotine/day for 10 days also showed significant elevations in brain KYNA. Hippocampal microdialysis, performed in animals receiving nicotine (1 mg/kg) for 10 days, revealed a significant increase in basal extracellular KYNA levels compared to controls, whereas acute treatment with this dose produced no such change. Measurements of KYNA's bioprecursor kynurenine in brain or blood did not reveal any nicotine-induced changes. These results indicate that nicotine has a brain-specific, biphasic effect on the transamination of kynurenine to KYNA. Such nicotine-induced fluctuations in brain KYNA may cause functional changes in processes that regulate glutamatergic and cholinergic neurotransmission in the normal and diseased brain.