Nicotine-induced excitation of locus coeruleus neurons is blocked by elevated levels of endogenous kynurenic acid

The present electrophysiological study shows that manipulation with endogen ous brain kynurenic acid (KYNA) is able to affect the response of central n oradrenergic neurons to nicotine. Previous studies have shown that systemic ally administered nicotine in low doses is associated with a marked, but sh ort-lasting increase in the firing rate of rat noradrenergic neurons in the locus coeruleus (LC). This action of nicotine is of peripheral origin and finally mediated via a release of glutamate within the LC. KYNA is an endog enous glutamate receptor antagonist, which shows an uneven distribution in human brain. Previous studies have shown that a potent inhibitor of kynuren ine 3-hydroxylase, PNU 156561A, is able to dose-dependently increase the le vels of KYNA in brain. Anesthetized rats were given PNU 156561A in a dose t hat caused a 5-fold increase in brain KYNA levels after 3-6 hours (40 mg/kg , i.v.). This treatment was found to abolish the increase in firing rate of LC neurons induced by nicotine (25-200 mu g/kg, i.v.). The results of the present study show that an increased concentration of endogenous brain KYNA is able to inhibit the activation of central noradrenergic neurons by nico tine. In addition, our results highlight the role of endogenous KYNA in bra in as a potentially important modulator of brain glutamatergic responses. S ynapse 37:104-108, 2000. (C) 2000 Wiley-Liss, Inc.