Olanzapine activates the rat locus coeruleus: In vivo electrophysiology and c-fos immunoreactivity

Background: Activation of central noradrenergic pathways by atypical antips ychotics has been hypothesized to play a role in their efficacy in treating the negative symptoms and cognitive impairment of schizophrenia. Because a cute administration of the atypical antipsychotic olanzapine has been shown to increase extracellular levels of norepinephrine in the medial prefronta l cortex, we examined the effects of olanzapine on the noradrenergic cells of the locus coeruleus (LC). Methods: The effects of olanzapine (0.25-16 mg kg(-1), IV) on the firing ra tes and patterns of LC neurons were determined by extracellular, single-uni t recordings in chloral hydrate-anaesthetized rats. The effects of olanzapi ne and clozapine on c-Fos expression in the LC, nucleus subcoeruleus part a lpha (SubCA), and nucleus A5 (A5) were studied by immunohistochemistry. Results: Olanzapine increased LC cell firing rates, deregularized firing, a nd induced burst firing. Induction of c-Fos expression in the LC by olanzap ine and clozapine was confirmed and was also found in the SubCA, but not in A5. Conclusions: Acute administration of olanzapine activates the noradrenergic neurons of the rat LC This increased activity of LC neurons may play an im portant role in the efficacy of olanzapine and clozapine in treating both t he negative symptoms and cognitive impairment observed in schizophrenic pat ients. Biol Psychiatry 2001;50:510-520 (C) 2001 Society of Biological Psych iatry.