Corticotropin (ACTH) acts directly on amygdala neurons to down-regulate corticotropin-releasing hormone gene expression

The hormone corticotropin (ACTH) is employed as therapy for diverse neurological disorders, but the mechanisms for its efficacy remain unknown. ACTH promotes the release of adrenal steroids (glucocorticoids), and most ACTH effects on the central nervous system (CNS) have been attributed to activatio...

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Bibliographic Details
Published in:Annals of neurology 2001-03, Vol.49 (3), p.304-312
Main Authors: Brunson, Kristen L., Khan, Najeeb, Eghbal-Ahmadi, Mariam, Baram, Tallie Z.
Format: Article
Language:English
Subjects:
Adrenocorticotropic Hormone - metabolism
Amygdala - metabolism
Amygdala - physiology
Animals
Biological and medical sciences
Corticotropin-Releasing Hormone - metabolism
Down-Regulation - physiology
Gene Expression Regulation
Medical sciences
Nervous system involvement in other diseases. Miscellaneous
Neurology
Neurons - metabolism
Rats
Rats, Sprague-Dawley
RNA, Messenger - analysis
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Summary:The hormone corticotropin (ACTH) is employed as therapy for diverse neurological disorders, but the mechanisms for its efficacy remain unknown. ACTH promotes the release of adrenal steroids (glucocorticoids), and most ACTH effects on the central nervous system (CNS) have been attributed to activation of glucocorticoid receptors. However, in several human disorders, ACTH has therapeutic actions that differ qualitatively or quantitatively from those of steroids. This study tested the hypothesis that ACTH directly influences limbic neurons via the recently characterized melanocortin receptors and focused on the effects of ACTH on the expression of corticotropin‐releasing hormone (CRH), a neuropeptide involved in neuroimmune functions and in certain developmental seizures. The results demonstrated that ACTH potently reduced CRH expression in amygdala neurons. This down‐regulation was not abolished by experimental elimination of steroids or by blocking their receptors and was reproduced by a centrally administered ACTH fragment that does not promote steroid release. Importantly, selective blocking of melanocortin receptors prevented ACTH‐induced down‐regulation of CRH expression. Taken together, these data indicate that ACTH activates central melanocortin receptors to modulate CRH gene expression in amygdala, supporting the notion that direct, steroid‐independent actions of ACTH may account for some of its established clinical effects on the CNS. Ann Neurol 2001;49:304–312
ISSN:0364-5134
1531-8249
DOI:10.1002/ana.66