The tryptophan metabolite kynurenic acid (KYNA) has long been recognized as
an NMDA receptor antagonist. Here, interactions between KYNA and the nicot
inic 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 th
e background perfusion. Exposure (greater than or equal to4 min) of culture
d hippocampal neurons to KYNA (greater than or equal to 100 nm) inhibited a
ctivation of somatodendritic alpha7 nAChRs; the IC50 for KYNA was similar t
o7 muM. The inhibition of alpha7 nAChRs was noncompetitive with respect to
the agonist and voltage independent. The slow onset of this effect could no
t be accounted for by an intracellular action because KYNA (1 mm) in the pi
pette solution had no effect on alpha7 nAChR activity. KYNA also blocked th
e activity of preterminal/presynaptic alpha7 nAChFs in hippocampal neurons
in cultures and in slices. NMDA receptors were less sensitive than alpha7 n
AChRs to KYNA. The IC50 values for KYNA-induced blockade of NMDA receptors
in the absence and presence of glycine (10 muM) were similar to 15 and 235
muM, respectively. Prolonged (3 d) exposure of cultured hippocampal neurons
to KYNA increased their nicotinic sensitivity, apparently by enhancing alp
ha4 beta2 nAChR expression. Furthermore, as determined by HPLC with fluores
cence detection, repeated systemic treatment of rats with nicotine caused a
transient reduction followed by an increase in brain KYNA levels. These re
sults demonstrate that nAChRs are targets for KYNA and suggest a functional
ly significant cross talk between the nicotinic cholinergic system and the
kynurenine pathway in the brain.