Effects of short-term and chronic olanzapine treatment on immediate early gene protein and tyrosine hydroxylase immunoreactivity in the rat locus coeruleus and medial prefrontal cortex

Abstract

Atypical antipsychotic drugs, such as olanzapine, have been reported to activate the locus coeruleus (LC) and lead to acute expression of the Fos-like immediate early gene (IEG) protein in the LC and medial prefrontal cortex (mPFC). Stimuli that activate the LC have been reported to increase expression of tyrosine hydroxylase (TH), the rate-limiting enzyme in catecholamine synthesis. However, the effects of chronic treatment with olanzapine on IEG expression and the dose-dependence of the effects of olanzapine on IEG and TH expression are not known. Thus, we examined Fos-like, c-Jun, activating transcription factor 2 (ATF-2), early growth response 1 (Egr-1), early growth response 2 (Egr-2), and TH immunoreactivity expression in the LC and mPFC in rats receiving 2, 4, 8, or 15 mg/kg/day olanzapine by s.c. osmotic minipump for 4 h, 1 week, 2 weeks, or 4 weeks. ATF-2 expression was up-regulated at all treatment durations, while Egr-1 and Egr-2 were down-regulated in both the LC and mPFC. Fos-like expression was up-regulated through 2 weeks, but not 4 weeks, in both the LC and mPFC. C-Jun expression was up-regulated for 4 weeks in the LC and for 2 weeks, but not 4 weeks, in the mPFC. At all doses, there were rapid and sustained increases in TH immunoreactivity in the LC, but only delayed increases in the mPFC. These data indicate that olanzapine has rapid effects on IEG in the LC and mPFC, many of which are sustained through four weeks of treatment. Further, these data indicate that the delayed increase in TH expression in the mPFC parallels, and may play an important role in, the increased efficacy of olanzapine that emerges over time in humans.