title: Activation of noradrenergic locus coeruleus neurons by clozapine and haloperidol: involvement of glutamatergic mechanisms.
abstract: The major brain noradrenergic nucleus locus coeruleus (LC) has long been thought to be involved in states of alertness and cognitive processes. These functional characteristics make this nucleus interesting with regard to the signs of schizophrenia, especially the negative symptoms of the disease. In the present in-vivo electrophysiological study we analyse a putative interaction between endogenous kynurenic acid (KYNA) and the antipsychotic drugs clozapine and haloperidol on noradrenergic LC neurons. Previous studies have shown that systemically administered antipsychotic drugs increase the neuronal activity of LC noradrenaline (NA) neurons. In line with these findings, our results show that clozapine (1.25-10 mg/kg i.v.) and haloperidol (0.05-0.08 mg/kg i.v.) increased the firing rate of LC NA neurons in anaesthetized rats. Pretreatment with PNU 156561A (40 mg/kg i.v., 3 h), a potent inhibitor of kynurenine 3-hydroxylase, produced a 2-fold increase in rat brain KYNA levels. This treatment prevented the increase in firing rate of LC NA neurons induced by haloperidol (0.05-0.08 mg/kg i.v.) and clozapine in high doses (2.5-10 mg/kg i.v.). However, the excitatory action of the lowest dose of clozapine (1.25 mg/kg i.v.) was not abolished by elevated levels of brain KYNA. Furthermore, pretreatment with L-701,324 (4 mg/kg i.v.) a selective antagonist at the glycine site of the NMDA receptor prevented the excitatory effects of both clozapine and haloperidol. The present results suggest that the excitation of LC NA neurons by haloperidol and clozapine involves a glutamatergic component.
authors.affiliation: Department of Physiology & Pharmacology, Karolinska Institutet, Stockholm, Sweden. Linda.Nilsson@fyfa.ki.se
authors.forename: Linda K
authors.initials: LK
authors.lastname: Nilsson
authors.forename: Lilly
authors.initials: L
authors.lastname: Schwieler
authors.forename: Göran
authors.initials: G
authors.lastname: Engberg
authors.forename: Klas R
authors.initials: KR
authors.lastname: Linderholm
authors.forename: Sophie
authors.initials: S
authors.lastname: Erhardt
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000704:Analysis of Variance; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D002087:Butyrates / Q000494:pharmacology; D003024:Clozapine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D018698:Glutamic Acid / Q000378:metabolism*; D006220:Haloperidol / Q000494:pharmacology*; D007736:Kynurenic Acid / Q000378:metabolism; D008125:Locus Coeruleus / Q000166:cytology*; D008297:Male; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D009638:Norepinephrine / Q000378:metabolism*; D015363:Quinolones / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D014150:Antipsychotic Agents; D002087:Butyrates; D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; C104254:FCE 28833; D015363:Quinolones; D018698:Glutamic Acid; D007736:Kynurenic Acid; C094635:L 701324; D003024:Clozapine; D006220:Haloperidol; D009638:Norepinephrine