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The Journal of Neuroscience, October 1, 2001, 21(19):7463-7473

The Brain Metabolite Kynurenic Acid Inhibits 7 Nicotinic Receptor Activity and Increases Non-7 Nicotinic Receptor Expression: Physiopathological Implications

Corey Hilmas¹, Edna F. R. Pereira¹, Manickavasagom Alkondon¹, Arash Rassoulpour², Robert Schwarcz^{1, 2}, and Edson X. Albuquerque^{1, 3}

¹ Department of Pharmacology and Experimental Therapeutics and ² Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore, Maryland 21201, and ³ Departamento de Farmacologia Básica e Clínica, Instituto de Ciências Biomédicas, Centro de Ciências da Saúde, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ 21944, Brazil

The tryptophan metabolite kynurenic acid (KYNA) has long been recognized as an NMDA receptor antagonist. Here, interactions between KYNA and the nicotinic system in the brain were investigated using the patch-clamp technique and HPLC. In the electrophysiological studies, agonists were delivered via a U-shaped tube, and KYNA was applied in admixture with agonists and via the background perfusion. Exposure (4 min) of cultured hippocampal neurons to KYNA (100 nM) inhibited activation of somatodendritic 7 nAChRs; the IC₅₀ for KYNA was ~7 µM. The inhibition of 7 nAChRs was noncompetitive with respect to the agonist and voltage independent. The slow onset of this effect could not be accounted for by an intracellular action because KYNA (1 mM) in the pipette solution had no effect on 7 nAChR activity. KYNA also blocked the activity of preterminal/presynaptic 7 nAChRs in hippocampal neurons in cultures and in slices. NMDA receptors were less sensitive than 7 nAChRs to KYNA. The IC₅₀ values for KYNA-induced blockade of NMDA receptors in the absence and presence of glycine (10 µM) were ~15 and 235 µM, respectively. Prolonged (3 d) exposure of cultured hippocampal neurons to KYNA increased their nicotinic sensitivity, apparently by enhancing 42 nAChR expression. Furthermore, as determined by HPLC with fluorescence detection, repeated systemic treatment of rats with nicotine caused a transient reduction followed by an increase in brain KYNA levels. These results demonstrate that nAChRs are targets for KYNA and suggest a functionally significant cross talk between the nicotinic cholinergic system and the kynurenine pathway in the brain.

Key words: nicotinic ACh receptors; NMDA receptors; hippocampus; kynurenic acid; electrophysiology; brain slices

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Copyright © 2001 Society for Neuroscience  0270-6474/01/21197463-11$05.00/0

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