Evidence of a corticotropin-releasing hormone pulse generator in the macaque hypothalamus

Abstract

The secretion of hormones from the hypothalamic-pituitary axis is, in general, characterized by an episodic pattern of release. In the adrenal axis, ACTH and cortisol levels in peripheral blood display irregularly pulsatile ultradian patterns that are superimposed on the well characterized circadian rhythm. While it is generally accepted that CRH is released from the hypothalamus in a similar manner, very few studies have actually examined the temporal release of CRH. To examine the temporal release of CRH directly, we have established an in vitro perifusion system using the hemisectioned macaque hypothalamus. Perifusate samples were collected at 10-min intervals for 20 h and assayed for CRH by RIA. In control animals, a very regular, pulsatile pattern of hormone release was present, with a pulse interval of 90 +/- 11 min. Although this interval closely approximates the average pulse interval of ACTH and cortisol in the human, the regular pattern revealed in our study has not been demonstrated previously in the adrenal axis in vivo and suggests that factors outside the hypothalamus play a major role in controlling adrenal hormone levels. When hypothalami were perifused with dexamethasone added to the culture medium, no change in pulsatile activity was detected, indicating that a site outside of the hypothalamus may function as the primary center of feedback inhibition by adrenal glucocorticoids in the central nervous system. Because the very regular pulses of CRH that we observed bear striking similarity to the circhoral pulses of GnRH, we speculate that CRH may play a more subordinate role in regulating the adrenal axis and that other releasing factors and/or feedback effects at the pituitary level may be more important in the generation of the irregularly pulsatile, circadian patterns of ACTH and cortisol seen in peripheral blood.

Characterizing Dynamic Interactions between Ultradian Glucocorticoid Rhythmicity and Acute Stress Using the Phase Response Curve

“…It is now clear that glucocorticoid pulsatility is important for dynamic transcriptional regulation of target genes in both the liver and the brain [2], [3], and these pulses therefore form the basis for an extremely rapid and sensitive hormone signalling system [4]. Whilst the pulsatile secretion of glucocorticoids has traditionally been assumed to result from the activity of neural pacemakers within the hypothalamus [5], [6], more recent theoretical findings suggest that the ultradian rhythm may in fact be regulated by pituitary-adrenal interactions, independent of pulsatile hypothalamic activity [7], [8].…”

Opioid and cocaine combined effect on cocaine-induced changes in HPA and HPG axes hormones in men

“…Several lines of evidence suggest that cocaine’s effects on ACTH may reflect stimulation of endogenous hypothalamic corticotropin-releasing factor (CRF). The amplitude of ACTH pulsatile release is controlled by CRF, and the frequency of ACTH pulses appears to reflect an intrinsic secretory rhythm of the anterior pituitary corticotrophs (Carnes et al, 1990; Gambacciani et al, 1987; Mershon et al, 1992). In preclinical studies, adrenalectomized rats did not learn to self-administer cocaine, and pharmacological blockade of corticosterone synthesis by metyrapone significantly decreased cocaine self-administration (Goeders and Guerin, 1996).…”

Unmasking ultradian rhythms in gene expression

“…When investigated in mammals, ultradian locomotor rhythmicity is independent of the central circadian clock, and brain substrates such as the retrochiasmatic area of the hypothalamus (16) and the midbrain dopaminergic system (12) have been found to be involved in driving these ultradian patterns. Moreover, ultradian rhythms in in vitro cell cultures have been reported for glucocorticoid release (17, 18), single-cell firing (19), and protein synthesis (20) suggesting that these rhythms are intrinsically driven at the cellular level, but mechanisms driving them remain unknown.…”