Prostaglandin F(2alpha) (PGF(2alpha)), represses ovarian steroidogenesis and initiates parturition in mammals but its impact on adrenal gland is unknown. Prostaglandins biosynthesis depends on the sequential action of upstream cyclooxygenases (COX) and terminal synthases but no PGF(2alpha) synthases (PGFS) were functionally identified in mammalian cells. In vitro, the most efficient mammalian PGFS belong to aldo-keto reductase 1B (AKR1B) family. The adrenal gland is a major site of AKR1B expression in both human (AKR1B1) and mouse (AKR1B3, AKR1B7). Thus, we examined the PGF(2alpha) biosynthetic pathway and its functional impact on both cortical and medullary zones. Both compartments produced PGF(2alpha) but expressed different biosynthetic isozymes. In chromaffin cells, PGF(2alpha) secretion appeared constitutive and correlated to continuous expression of COX1 and AKR1B3. In steroidogenic cells, PGF(2alpha) secretion was stimulated by adrenocorticotropic hormone (ACTH) and correlated to ACTH-responsiveness of both COX2 and AKR1B7/B1. The pivotal role of AKR1B7 in ACTH-induced PGF(2alpha) release and functional coupling with COX2 was demonstrated using over- and down-expression in cell lines. PGF(2alpha) receptor was only detected in chromaffin cells, making medulla the primary target of PGF(2alpha) action. By comparing PGF(2alpha)-responsiveness of isolated cells and whole adrenal cultures, we demonstrated that PGF(2alpha) repressed glucocorticoid secretion by an indirect mechanism involving a decrease in catecholamine release which in turn decreased adrenal steroidogenesis. PGF(2alpha) may be regarded as a negative autocrine/paracrine regulator within a novel intra-adrenal feedback loop. The coordinated cell-specific regulation of COX2 and AKR1B7 ensures the generation of this stress-induced corticostatic signal.

The synthesis of a series of aminoethylbiphenyls as novel 5-HT(7) receptor ligands is described. The novel derivatives exhibit high affinity for the 5-HT(7) receptor with selectivity toward 5-HT(1A) receptor.

CONTEXT:Neurotensin (NT) modulates corticosteroid secretion from the mammalian adrenal gland.OBJECTIVE:The objective of this study was to investigate the possible involvement of NT in the control of cortisol secretion in the human adrenal gland.DESIGN:In vitro studies were conducted on cultured human adrenocortical cells.SETTING:This study was conducted in a university research laboratory.PATIENTS:Adrenal explants from patients undergoing expanded nephrectomy for kidney cancer were studied.MAIN OUTCOME MEASURE:Cortisol secretion from cultured adrenocortical cells was measured.RESULTS:NT1-11, the N-terminal fragment of NT, dose-dependently inhibited basal and ACTH-stimulated cortisol production by human adrenocortical cells in primary culture. In contrast, NT had no influence on cortisol output at concentrations up to 10(-6) m. HPLC and RT-PCR analyses failed to detect any significant amounts of NT and NT mRNA, respectively, in adrenal extracts. Molecular and pharmacological studies were performed to determine the type of NT receptor involved in the corticostatic effect of NT1-11. RT-PCR analysis revealed the expression of NT receptor type (NTR) 3 mRNA but not NTR1 and NTR2 mRNAs in the human adrenal tissue. However, the pharmacological profile of the adrenal NT1-11 receptor was different from that of NTR3, indicating that this receptor type is not involved in the action of NT1-11 on corticosteroidogenesis.CONCLUSION:Our results indicate that NT1-11 may act as an endocrine factor to inhibit cortisol secretion through activation of a receptor distinct from the classical NTR1, NTR2, and NTR3.

Virtual screening studies have identified a series of phenylpyrroles as novel 5-HT7 receptor ligands. The synthesis and the affinity for the 5-HT7 receptor of these phenylpyrroles are described. Some of these compounds exhibited high affinity for the 5-HT7 receptors.

Blood corticosterone levels (CORT) were measured before and after the completion of the elevated +-maze test in cerebellar Lurcher mutant and control mice. Consistent with the existence of a much more pronounced activation of the hypothalamo-pituitary-adrenal (HPA) system in the mutants, our results showed that while basal CORT were similar in mutants and controls, the surge of this stress indicator was enhanced in the Lurcher mice after completion of a behavioral test of anxiety. In contrast, at the behavioral level, we also observed that Lurcher exhibited significantly reduced anxiety related indices; they spent a significant greater amount of time in the aversive places of the apparatus and entered them more frequently than non mutant mice. It is proposed that rather than less anxious, the Lurcher mice are less inhibited than controls when placed in anxiogenic situation and that such poor inhibition could be causally related to changes in HPA system regulation. The overall patterns of our behavioral and endocrinological results thereby provided the evidence that cerebellar circuitry is involved in producing changes in physiological and behavioral stress-related emotional responses.

ChemInformVolume 35, Issue 31 Other Subjects Molecular Design Based on 3D Pharmacophores. Applications to 5-HT7 Receptors. Alban Lepailleur, Alban Lepailleur Cent. Etud. Rech. Med. Normandie, UFR Sci. Pharm., Univ. Caen, F-14032 Caen, Fr.Search for more papers by this authorRonan Bureau, Ronan Bureau Cent. Etud. Rech. Med. Normandie, UFR Sci. Pharm., Univ. Caen, F-14032 Caen, Fr.Search for more papers by this authorStephane Lemaitre, Stephane Lemaitre Cent. Etud. Rech. Med. Normandie, UFR Sci. Pharm., Univ. Caen, F-14032 Caen, Fr.Search for more papers by this authorFrancois Dauphin, Francois Dauphin Cent. Etud. Rech. Med. Normandie, UFR Sci. Pharm., Univ. Caen, F-14032 Caen, Fr.Search for more papers by this authorJean-Charles Lancelot, Jean-Charles Lancelot Cent. Etud. Rech. Med. Normandie, UFR Sci. Pharm., Univ. Caen, F-14032 Caen, Fr.Search for more papers by this authorVincent Contesse, Vincent Contesse Cent. Etud. Rech. Med. Normandie, UFR Sci. Pharm., Univ. Caen, F-14032 Caen, Fr.Search for more papers by this authorSebastien Lenglet, Sebastien Lenglet Cent. Etud. Rech. Med. Normandie, UFR Sci. Pharm., Univ. Caen, F-14032 Caen, Fr.Search for more papers by this authorCatherine Delarue, Catherine Delarue Cent. Etud. Rech. Med. Normandie, UFR Sci. Pharm., Univ. Caen, F-14032 Caen, Fr.Search for more papers by this authorHubert Vaudry, Hubert Vaudry Cent. Etud. Rech. Med. Normandie, UFR Sci. Pharm., Univ. Caen, F-14032 Caen, Fr.Search for more papers by this authorSylvain Rault, Sylvain Rault Cent. Etud. Rech. Med. Normandie, UFR Sci. Pharm., Univ. Caen, F-14032 Caen, Fr.Search for more papers by this author Alban Lepailleur, Alban Lepailleur Cent. Etud. Rech. Med. Normandie, UFR Sci. Pharm., Univ. Caen, F-14032 Caen, Fr.Search for more papers by this authorRonan Bureau, Ronan Bureau Cent. Etud. Rech. Med. Normandie, UFR Sci. Pharm., Univ. Caen, F-14032 Caen, Fr.Search for more papers by this authorStephane Lemaitre, Stephane Lemaitre Cent. Etud. Rech. Med. Normandie, UFR Sci. Pharm., Univ. Caen, F-14032 Caen, Fr.Search for more papers by this authorFrancois Dauphin, Francois Dauphin Cent. Etud. Rech. Med. Normandie, UFR Sci. Pharm., Univ. Caen, F-14032 Caen, Fr.Search for more papers by this authorJean-Charles Lancelot, Jean-Charles Lancelot Cent. Etud. Rech. Med. Normandie, UFR Sci. Pharm., Univ. Caen, F-14032 Caen, Fr.Search for more papers by this authorVincent Contesse, Vincent Contesse Cent. Etud. Rech. Med. Normandie, UFR Sci. Pharm., Univ. Caen, F-14032 Caen, Fr.Search for more papers by this authorSebastien Lenglet, Sebastien Lenglet Cent. Etud. Rech. Med. Normandie, UFR Sci. Pharm., Univ. Caen, F-14032 Caen, Fr.Search for more papers by this authorCatherine Delarue, Catherine Delarue Cent. Etud. Rech. Med. Normandie, UFR Sci. Pharm., Univ. Caen, F-14032 Caen, Fr.Search for more papers by this authorHubert Vaudry, Hubert Vaudry Cent. Etud. Rech. Med. Normandie, UFR Sci. Pharm., Univ. Caen, F-14032 Caen, Fr.Search for more papers by this authorSylvain Rault, Sylvain Rault Cent. Etud. Rech. Med. Normandie, UFR Sci. Pharm., Univ. Caen, F-14032 Caen, Fr.Search for more papers by this author First published: 08 July 2004 https://doi.org/10.1002/chin.200431201AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article. Volume35, Issue31August 03, 2004 RelatedInformation

We have previously shown that serotonin (5-HT) stimulates aldosterone secretion from the human adrenal gland through activation of 5-HT4 receptors. The aim of the present study was to investigate in vivo and in vitro the presence of 5-HT4 receptors in aldosterone-producing adenomas (aldosteronomas). Eight patients with aldosteronoma received a single oral dose of placebo or cisapride (10 mg). Cisapride administration significantly increased plasma aldosterone within 120 min without any significant change in renin, cortisol, or potassium levels. In two patients, a marked decrease in the plasma aldosterone response to cisapride was observed after surgical removal of the tumor. The effects of 5-HT and selective 5-HT4 ligands on aldosterone production from aldosteronoma tissues were studied in vitro using a perifusion system technique. 5-HT and the 5-HT4 receptor agonist cisapride (10−7m, 20 min) both stimulated aldosterone secretion from aldosteronoma slices. The 5-HT- and cisapride-evoked aldosterone responses were inhibited by concomitant administration of the specific 5-HT4 receptor antagonist GR 113808 (10−7m, 150 min). PCR amplification revealed the expression of 5-HT4 receptor mRNA in 13 of 14 aldosteronomas studied. Taken together, these data show that most aldosteronomas, like normal glomerulosa cells, express a functional 5-HT4 receptor. Our results also suggest that 5-HT, which can be locally released by intratumoral mast cells, may play a role in the pathophysiology of these tumors.

Early stimulation by environmental enrichment generally leads to improved learning abilities in rodents. However, the effects of environmental enrichment on emotional reactivity remain more questionable and were mostly studied by using classical tests of anxiety based on confrontation with a novel environment. The main goal of our study was to use different tests of anxiety to compare BALB/c mice reared in either a standard condition (SC) or enriched condition (EC). Exposure to cat feces was used to assess anxiety according to an ethoexperimental approach and a comparison was made with the elevated plus maze and the open field as classical tests of anxiety. In accordance with previous works, our results show that EC mice were more active than SC mice in the elevated plus maze and the open field. Thus, possibly as a direct consequence of frequent changes in their breeding conditions, reactivity to a novel environment was reduced in EC mice. However, the cat odor test revealed no intergroup differences for behavior, although corticosterone levels were reduced in EC mice. These results indicate that classical (i.e. reaction to novel environments) and ethoexperimental-based tests (i.e. exposure to predator cues) measure different aspects of emotional reactivity. Further studies using ECs should be useful for the delineation of the neurobiological substrates of these different reactions.

Serotonin (5-HT) stimulates aldosterone secretion in man through activation of 5-HT4 receptors coupled to adenylyl cyclase via a Gs regulatory protein. In adrenocortical cells, the levels of expression of the Gs protein and ACTH receptor are decreased when the cells are deprived of ACTH and angiotensin II (ANG II). In order to examine the possible influence of ACTH and ANG II on the responsiveness of human glomerulosa cells to 5-HT, we have investigated the effect of cisapride, a 5-HT4 receptor agonist, on plasma aldosterone in patients with suppressed plasma ACTH, i.e. patients with corticotropic insufficiency (CI), and in patients with suppressed renin-ANG II activity, i.e. patients with primary hyperaldosteronism (PH) including both aldosterone-producing adenoma and idiopathic hyperaldosteronism. After 2 h of recumbency, all patients received a single oral dose of 10 mg cisapride. In the CI group, cisapride induced a 5-fold increase in plasma aldosterone levels without any modification of plasma renin, potassium or cortisol levels. Combined administration of cisapride and ACTH caused an increase in plasma aldosterone similar to that produced by ACTH alone. In the PH group, cisapride was still able to cause a 3.6-fold increase in plasma aldosterone levels while renin remained suppressed throughout the study. Taken together, these data show that cisapride stimulates aldosterone secretion in CI and PH patients, indicating that prolonged suppression of plasma ACTH or renin-ANG II activity does not affect the sensitivity of glomerulosa cells to 5-HT. The present study also demonstrates that the stimulatory effects of 5-HT and ACTH on aldosterone secretion are not additive.