Nicotine-induced excitation of locus coeruleus neurons is blocked by elevated levels of endogenous kynurenic acid.
The present electrophysiological study shows that manipulation with endogenous brain kynurenic acid (KYNA) is able to affect the response of central noradrenergic neurons to nicotine. Previous studies have shown that systemically administered nicotine in low doses is associated with a marked, but short-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 endogenous glutamate receptor antagonist, which shows an uneven distribution in human brain. Previous studies have shown that a potent inhibitor of kynurenine 3-hydroxylase, PNU 156561A, is able to dose-dependently increase the levels of KYNA in brain. Anesthetized rats were given PNU 156561A in a dose that 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 microg/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 nicotine. In addition, our results highlight the role of endogenous KYNA in brain as a potentially important modulator of brain glutamatergic responses.
Erhardt
S
S
Department of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden. sophie.erhardt@fyfa.ki.se
Hajos
M
M
Lindberg
A
A
Engberg
G
G
D000818:Animals; D002087:Butyrates / Q000494:pharmacology; D003505:Cyclodextrins / Q000494:pharmacology; D004594:Electrophysiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005731:Ganglionic Stimulants / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D007736:Kynurenic Acid / Q000378:metabolism*; D008125:Locus Coeruleus / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D008297:Male; D009474:Neurons / Q000187:drug effects* / Q000502:physiology*; D009538:Nicotine / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D047392:beta-Cyclodextrins
D002087:Butyrates; D003505:Cyclodextrins; D004791:Enzyme Inhibitors; C104254:FCE 28833; D005731:Ganglionic Stimulants; D047392:beta-Cyclodextrins; D009538:Nicotine; D007736:Kynurenic Acid; C031215:betadex