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Repeated treatment of rats with antidepressant drugs down-regulates tyrosine hydroxylase (TH) in the locus coeruleus (LC). Using this effect as a model system, this study evaluated the antidepressant potential of the atypical antipsychotic drug, olanzapine. In an initial study, rats were treated i.p. with saline, olanzapine (3 mg/kg), or imipramine (15 mg/kg) once daily for 18 d. Three additional groups of rats received the same treatments that were overlapped with reserpine administration (0.5 mg/kg.d for 21 d). In a second study, groups of rats were treated twice daily with saline, olanzapine (5 mg/kg.d), fluoxetine (15 mg/kg.d), or fluoxetine (15 mg/kg.d) plus olanzapine (5 mg/kg.d) for 1, 6, 12 and 18 d. In the initial study, imipramine produced a 45% reduction in LC TH levels, while olanzapine had no effect. In reserpinized rats, olanzapine exhibited an action that was opposite to that of imipramine, although this effect did not reach statistical significance. In the second study, olanzapine treatment alone or in combination with fluoxetine up-regulated TH in the LC, while fluoxetine alone had no effect. When fluoxetine was co-administered, olanzapine-induced increases in LC TH were more robust and occurred earlier in the time-course of treatment. Based on this preclinical model alone, olanzapine did not exhibit typical antidepressant properties. The unique effect of olanzapine to elevate LC TH may result from olanzapine-induced increases in LC activity. Such an action may contribute to novel behavioural effects of this atypical antipsychotic drug, including enhanced attention.

Effect of repeated treatment with olanzapine or olanzapine plus fluoxetine on tyrosine hydroxylase in the rat locus coeruleus