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

Abstract

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 corticotropinreleasing 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.The hormone corticotropin (ACTH) has been used extensively to treat neurological disorders. In some auto-immune disorders (eg, opsoclonus-myoclonus) and in certain developmental seizure disorders (eg, infantile spasms), ACTH possesses increased efficacy or a different spectrum of effects compared to adrenal steroids. [1][2][3][4] However, the mechanisms for these singular actions of ACTH on the central nervous system (CNS) have remained unresolved. 1,5 Native ACTH is synthesized in the pituitary and functions to stimulate the adrenal cortex to release steroids into the blood stream as part of the neuroendocrine stress response. Neurons containing ACTH have been localized to the CNS, particularly the hypothalamus, and ACTHimmunoreactive cell bodies or fibers have also been described in amygdala, cerebral cortex, brainstem, and cerebellum. 6,7 In contrast to pituitary ACTH, the functions of CNS ACTH have not been well-defined. Evidence from both human and animal studies has suggested that CNS ACTH may function as a neurotransmitter/neuromodulator. The goal of the current studies was to examine whether ACTH directly influenced CRH gene expression in the immature rat amygdala. Because steroids also regulate CRH expression in this region, this study focused on discerning steroid-independent effects, testing the hypothesis that ACTH suppresses CRH expression in amygdaloid central nucleus (ACe) directly, via activation of central melanocortin receptors. Materials and Methods Materials Experimental DesignSeveral experiments were carried out to test the hypothesis that ACTH al...

Neonatal melanocortin receptor agonist treatment reduces play fighting and promotes adult attachment in prairie voles in a sex-dependent manner

“…However, MTII acting directly on adrenal MC2R likely increases corticosterone release in comparison to the selective MC4R agonist PF446687, and the heightened stress activation may counteract effects on adult prosociality in MTII-treated male voles. Additionally, MC4R stimulation in the central amygdala leads to reductions in CRF mRNA (Brunson et al, 2001). It is therefore possible that the modulation of stress axis by MC4R underlies the observed changes in adult sociality.…”

Inflammation in Epileptic Encephalopathies

“…Previous studies have suggested immunosuppressive effect of ACTH and corticosteroids, together with anti-inflammatory properties, as well as direct inhibitory impact on CNS excitability and possible inhibition of endogenous proconvulsant factor synthesis (Baram & Hatalski 1998, Riikonen 2000, Brunson, Khan, Eghbal-Ahmadi & Baram 2001, Joels & Baram 2009, Vezzani, French, Bartfai & Baram 2011), although ACTH has been reported to be more efficient (Snead 2001). In addition, therapy with immune-modulatory agents such as ACTH and corticosteroids or high-dose immunoglobulin has shown efficacy on spasms cessation in some patients with IS of infectious etiology, however it was suggested that steroid therapy should be avoided in patients with a history of CMV and herpes simplex in the past (Ariizumi, Shiihara, Hibio, Ryo, Baba, Ogawa et al 1983, Ariizumi, Baba, Hibio, Shiihara, Michihiro, Ogawa et al 1987, Riikonen 1993, Wise, Rutledge & Kuzniecky 1996, Hattori 2001).…”

Adrenocorticotropic hormone protects learning and memory function in epileptic Kcna1 -null mice

“…In support of this, one study has shown that a single i.p. injection of a high dose of ACTH 4-10 (80 IU/Kg) – having a high affinity for melanocortin receptors - reduced CRF mRNA receptor expression in the central nucleus of the amygdala [25]. This effect was blocked by the melanocortocotropin MC4 receptor antagonist SHU919, indicating that activation of melanocortin receptors are responsible for the effect of ACTH in reducing CRF receptor expression in the amygdala [25].…”

“…injection of a high dose of ACTH 4-10 (80 IU/Kg) – having a high affinity for melanocortin receptors - reduced CRF mRNA receptor expression in the central nucleus of the amygdala [25]. This effect was blocked by the melanocortocotropin MC4 receptor antagonist SHU919, indicating that activation of melanocortin receptors are responsible for the effect of ACTH in reducing CRF receptor expression in the amygdala [25]. Furthermore, a recent study has shown that activation of MC4 receptors located post-synaptically in the hippocampus results in enhanced LTP due to a protein kinase A-dependent up-regulation in the surface expression of GluA1-containing AMPA receptors which are involved in the morphological maturation and number of dendritic spines [26].…”