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 neurolo gical disorders, but the mechanisms for its efficacy remain unknown. ACTH p romotes the release of adrenal steroids (glucocorticoids), and most ACTH ef fects on the central nervous system (CNS) have been attributed to activatio n of glucocorticoid receptors. However, in several human disorders, ACTH ha s therapeutic actions that differ qualitatively or quantitatively from thos e of steroids. This study tested the hypothesis that ACTH directly influenc es limbic neurons via the recently characterized melanocortin receptors and focused on the effects of ACTH on the expression of corticotropin-releasin g hormone (CRH), a neuropeptide involved in neuroimmune functions and in ce rtain developmental seizures. The results demonstrated that ACTH potently r educed CRH expression in amygdala neurons. This down-regulation was not abo lished by experimental elimination of steroids or by blocking their recepto rs and was reproduced by a centrally administered ACTH fi fragment that doe s not promote steroid release. Importantly, selective blocking of melanocor tin receptors prevented ACTH-induced down-regulation of CRH expression. Tak en together, these data indicate that ACTH activates central melanocortin r eceptors to modulate CRH gene expression in amygdala, supporting the notion that direct, steroid-independent actions of ACTH may account for some of i ts established clinical effects on the CNS.