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

被引:87
作者
Brunson, KL
Khan, N
Eghbal-Ahmadi, M
Baram, TZ
机构
[1] Univ Calif Irvine, Dept Pediat, Irvine, CA 92697 USA
[2] Univ Calif Irvine, Dept Anat Neurobiol & Neurol, Irvine, CA 92697 USA
关键词
D O I
10.1002/ana.66
中图分类号
R74 [神经病学与精神病学];
学科分类号
摘要
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 fi 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.
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页码:304 / 312
页数:9
相关论文
共 52 条
[1]   Brain melanocortin receptors: From cloning to function [J].
Adan, RAH ;
Gispen, WH .
PEPTIDES, 1997, 18 (08) :1279-1287
[2]  
Baram TZ, 1996, PEDIATRICS, V97, P375
[3]   CORTICOTROPIN-RELEASING HORMONE INDUCED SEIZURES IN INFANT RATS ORIGINATE IN THE AMYGDALA [J].
BARAM, TZ ;
HIRSCH, E ;
SNEAD, OC ;
SCHULTZ, L .
ANNALS OF NEUROLOGY, 1992, 31 (05) :488-494
[4]   Neuropeptide-mediated excitability: a key triggering mechanism for seizure generation in the developing brain [J].
Baram, TZ ;
Hatalski, CG .
TRENDS IN NEUROSCIENCES, 1998, 21 (11) :471-476
[5]   PATHOPHYSIOLOGY OF MASSIVE INFANTILE SPASMS - PERSPECTIVE ON THE PUTATIVE ROLE OF THE BRAIN ADRENAL AXIS [J].
BARAM, TZ .
ANNALS OF NEUROLOGY, 1993, 33 (03) :231-236
[6]   Infantile spasms: Hypothesis-driven therapy and pilot human infant experiments using corticotropin-releasing hormone receptor antagonists [J].
Baram, TZ ;
Mitchell, WG ;
Brunson, K ;
Haden, E .
DEVELOPMENTAL NEUROSCIENCE, 1999, 21 (3-5) :281-289
[7]   BRAIN-ADRENAL AXIS HORMONES ARE ALTERED IN THE CSF OF INFANTS WITH MASSIVE INFANTILE SPASMS [J].
BARAM, TZ ;
MITCHELL, WG ;
SNEAD, OC ;
HORTON, EJ ;
SAITO, M .
NEUROLOGY, 1992, 42 (06) :1171-1175
[8]   ACTH DOES NOT CONTROL NEONATAL SEIZURES INDUCED BY ADMINISTRATION OF EXOGENOUS CORTICOTROPIN-RELEASING HORMONE [J].
BARAM, TZ ;
SCHULTZ, L .
EPILEPSIA, 1995, 36 (02) :174-178
[9]   The in vivo proconvulsant effects of corticotropin releasing hormone in the developing rat are independent of ionotropic glutamate receptor activation [J].
Brunson, KL ;
Schultz, L ;
Baram, TZ .
DEVELOPMENTAL BRAIN RESEARCH, 1998, 111 (01) :119-128
[10]  
CROFFORD LJ, 1993, J IMMUNOL, V151, P1587