The antidepressants fluoxetine, idazoxan and phenelzine alter corticotropin-releasing hormone and tyrosine hydroxylase mRNA levels in rat brain: therapeutic implications
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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) reuptake inhibitor fluoxetine, the selective alpha 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
occurred 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 mineralocorticoid 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.(ABSTRACT TRUNCATED
AT 250 WORDS)