The antidepressants fluoxetine, idazoxan and phenelzine alter corticotropin-releasing hormone and tyrosine hydroxylase mRNA levels in rat brain: therapeutic implications

Abstract

Various classes of antidepressant drugs with distinct pharmacologic actions are differentially effective in the treatment of classic melancholic depression — characterized by pathological hyperarousal and atypical depression — associated with lethargy, hypersomnia, and hyperphagia. All antidepressant agents exert their therapeutic efficacy only after prolonged administration. In situ hybridization histochemistry was used to examine in rats the effects of short-term (2 weeks) and long-term (8 weeks) administration of 3 different classes of activating antidepressant drugs which tend to be preferentially effective in treating atypical depressions, on the expression of central nervous system genes thought to be dysregulated in major depression. Daily administration (5 mg/kg, i.p.) of the selective 5-hydroxytryptophan (5-HT) re-uptake inhibitor fluoxetine, the selective α 2-adrenergic receptor antagonist idazoxan, and the nonspecific monoamine oxidase A and B inhibitor phenelzine increased tyrosine hydroxylase mRNA levels by 70–150% in the locus coeruleus after 2 weeks of drug and by 71–115% after 8 weeks. The 3 drugs decreased corticotropin-releasing hormone mRNA levels by 30–48% in the paraventricular nucleus of the hypothalamus. The decreases occured at 8 weeks but not at 2 weeks. No consistent change in steroid hormone receptor mRNA levels was seen in the hippocampus with the 3 drugs, but fluoxetine and idazoxan increased the level of mineralcorticoid receptor (MR) and glucocorticoid receptor (GR) mRNA, respectively, after 8 weeks of drug administration. Proopiomelanocortin (POMC) mRNA levels in the anterior pituitary and plasma adrenocorticotropic-hormone (ACTH) levels were not altered after 2 or 8 weeks of drug treatment. Plasma corticosterone levels were decreased by all 3 drugs at the 2-week time point, and corticosterone continued to be reduced in the phenelzine-trated animals after 8 weeks of chronic drug administration. We have preivously demonstrated that the prototypic antidepressant imipramine shares with fluoxetine, idazoxan, and phenelzine the property of decreasing the expression of corticotropin-releasing hormone mRNA in the paraventricular nucleus after chronic administration. In contrast, imipramine, which is preferentially effective in treating melancholic depression, produces a significant decrease in tyrosine hydroxylase mRNA levels in the locus coeruleus as opposed to the effect of the other 3 drugs. Thus, our data suggest that the preferential efficacy of activating antidepressants in atypical depression may reflect a capacity to increase the expression of tyrosine hydroxylase mRNA in the locus coeruleus, an effect that could theoretically be utilized in the screening of pharmacologic agents for the treatment of this disorder. Overall, the data suggest that a reduction in the expression of corticotropin-releasing hormone mRNA in the paraventricular nucleus may be one common element relevant to the therapeutic efficacy of antidepressant drugs in the treatment of various forms of major depression.