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ABSTRACT: We have examined the effects of acute administration of the cannabinoid receptor type 1 (CB(1)) antagonist AM251 on the rat hypothalamic-pituitary-adrenal (HPA) axis with respect to both gender and time of day. Blood samples were collected from conscious male and female rats every 5 min using an automated blood sampling system, and corticosterone concentrations were determined. In male rats, there was a distinct diurnal effect of AM251 with a greater activation of the HPA axis in the morning (diurnal trough) compared with the evening (diurnal peak). At both times of the day, circulating corticosterone concentrations were elevated for approximately 4 h after AM251 administration. In female rats, there was also diurnal variation in the activation of the HPA axis; however, these effects were not as profound as those in males. Corticosterone concentrations were only slightly elevated at the diurnal trough and for a shorter time period than in males (2 compared with 4 h). Moreover, there was no effect of AM251 on corticosterone concentrations when administered at the diurnal peak. Subsequent studies, only in males, in which both ACTH and corticosterone were measured, confirmed that the effects of AM251 on corticosterone were mediated by ACTH. Moreover, the elevation of both ACTH and corticosterone could be replicated using another CB(1) antagonist, AM281. These data demonstrate that the extent and duration of HPA axis activation after CB(1) blockade are clearly dependent on both gender and time of day.
Endocrinology 08/2010; 151(8):3720-7. · 4.46 Impact Factor
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ABSTRACT: The inhibitory effect of androgens on the hypothalamic-pituitary-adrenal (HPA) axis in basal and stress conditions in adult male rats is well documented. Major sex-related neuroendocrine changes take place during puberty. There is a robust rise in production and secretion of gonadal steroids, which is thought to underlie numerous neural and behavioural changes brought on after puberty. The present study investigated the effect of the pubertal rise in gonadal steroid levels on the subsequent adult corticosterone profile, particularly the sensitivity of the adult HPA axis to testosterone. Animals were castrated either prepubertally (28 days) or in adulthood (11 weeks) and adult animals were subsequently treated with subcutaneous implants containing either testosterone or cholesterol. Using an automated blood sampling system, blood was collected from each freely moving, conscious rat every 10 min (i) over a 24 h period; (ii) in response to 10 min of noise stress, and (iii) following an immunological challenge with lipopolysaccharide (LPS). Analysis revealed that testosterone treatment did not significantly affect overall corticosterone release over the 24 h period in adult animals castrated before puberty in contrast to animals castrated in adulthood in which testosterone significantly suppressed corticosterone secretion. Following either a noise stress or LPS injection, testosterone treatment did not affect the hypothalamic or adrenal stress response in animals castrated prepubertally. Testosterone significantly suppressed the corticotrophin-releasing hormone and arginine vasopressin mRNA as well as the corticosterone response to LPS in castrated animals that had had their testes intact over puberty. These data provide evidence that puberty is a critical organizational period during which rising levels of gonadal steroids programme the sensitivity of the adult HPA axis to gonadal steroids in adulthood.
The Journal of Physiology 05/2009; 587(Pt 12):2977-85. · 4.72 Impact Factor
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ABSTRACT: Circulating corticosterone levels show an ultradian rhythm resulting from the pulsatile release of glucocorticoid hormone by the adrenal cortex. Because the pattern of hormone availability to corticosteroid receptors is of functional significance, it is important to determine whether there is also a pulsatile pattern of corticosterone concentration within target tissues such as the brain. Furthermore, it is unclear whether measurements of plasma corticosterone levels accurately reflect corticosterone levels in the brain. Given that the hippocampus is a principal site of glucocorticoid action, we investigated in male rats hippocampal extracellular corticosterone concentrations under baseline and stress conditions using rapid-sampling in vivo microdialysis. We found that hippocampal extracellular corticosterone concentrations show a distinct circadian and ultradian rhythm. The PULSAR algorithm revealed that the pulse frequency of hippocampal corticosterone is 1.03 +/- 0.07 pulses/h between 0900 and 1500 h and is significantly higher between 1500 and 2100 h (1.31 +/- 0.05). The hippocampal corticosterone response to stress is stressor dependent but resumes a normal ultradian pattern rapidly after the termination of the stress response. Similar observations were made in the caudate putamen. Importantly, simultaneous measurements of plasma and hippocampal glucocorticoid levels showed that under stress conditions corticosterone in the brain peaks 20 min later than in plasma but clears concurrently, resulting in a smaller exposure of the brain to stress-induced hormone than would be predicted by plasma hormone concentrations. These data are the first to demonstrate that the ultradian rhythm of corticosterone is maintained over the blood-brain barrier and that tissue responses cannot be reliably predicted from the measurement of plasma corticosterone levels.
Endocrinology 08/2008; 149(7):3244-53. · 4.46 Impact Factor
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ABSTRACT: The aim of this study was to investigate fast corticosteroid feedback of the hypothalamic-pituitary-adrenal (HPA) axis under basal conditions, in particular the role of the mineralocorticoid receptor. Blood samples were collected every 5 min from conscious rats at the diurnal peak, using an automated blood sampling system, and assayed for corticosterone. Feedback inhibition by rapidly increasing concentrations of ligand was achieved with an intravenous bolus of exogenous corticosteroid. This resulted in a significant reduction in plasma corticosterone concentrations within 23 min of the aldosterone bolus and 28 min of methylprednisolone. Evaluation of the pulsatile secretion of corticosterone revealed that the secretory event in progress at the time of administration of exogenous steroid was unaffected, whereas the next secretory event was inhibited by both aldosterone and methylprednisolone. The inhibitory effect of aldosterone was limited in duration (1 secretory event only), whereas that of methylprednisolone persisted for 4-5 h. Intravenous administration of canrenoate (a mineralocorticoid receptor antagonist) also had rapid effects on the HPA axis, with an elevation of ACTH within 10 min and corticosterone within 20 min. The inhibitory effect of aldosterone was unaffected by pretreatment with the glucocorticoid receptor antagonist RU-38486 but blocked by the canrenoate. These data imply an important role for the mineralocorticoid receptor in fast feedback of basal HPA activity and suggest that mineralocorticoids can dynamically regulate basal corticosterone concentrations during the diurnal peak, a time of day when there is already a high level of occupancy of the cytoplasmic mineralocorticoid receptor.
AJP Endocrinology and Metabolism 07/2008; 294(6):E1011-22. · 4.75 Impact Factor
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ABSTRACT: Glucocorticoids are secreted in discrete pulses resulting in an ultradian rhythm in all species that have been studied. In the rat there is an approximately hourly rhythm of corticosterone secretion, which appears to be regulated by alternating activation and inhibition of the HPA axis. At the level of signal transduction, the response to these pulses of corticosterone is determined by its dynamic interaction with the two transcription factors--the glucocorticoid and mineralocorticoid receptors. While the mineralocorticoid receptor remains activated throughout the ultradian cycle, the glucocorticoid receptor shows a phasic response to each individual pulse of corticosterone. This phasic response is regulated by an intranuclear proteasome-dependent rapid downregulation of the activated glucocorticoid receptor.
European Journal of Pharmacology 05/2008; 583(2-3):255-62. · 2.52 Impact Factor
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ABSTRACT: Timing is a critical factor in neuroendocrinology. Despite this, the temporal aspects of glucocorticoid signaling in the regulation of in vivo targets have been largely overlooked. Here, we present data showing that plasma glucocorticoid levels differ greatly from the constant signal predominantly used in cell culture experiments. Using an automated blood sampling system, we found that under basal conditions in nonstressed rats, corticosterone release occurs in discrete pulses of various amplitudes dependent on the circadian cycle. This basal pattern changes to a prolonged elevated nonpulsatile release in response to stressful stimuli. We have been able to recapitulate these different patterns of corticosterone presentation (short pulse vs. prolonged elevation) in adrenalectomized rats, and show that each pattern results in differential activation of hippocampal glucocorticoid and mineralocorticoid receptors. Finally, we provide evidence for a rapid proteasome-dependent clearance of activated glucocorticoid receptors, but not mineralocorticoid receptors, as a novel mechanism to allow dynamic interaction with rapidly changing physiological and environmental conditions.
Endocrinology 12/2007; 148(11):5470-7. · 4.46 Impact Factor
