Elabela and Apelin actions in healthy and pathological pregnancies.

Pregnancy is a dynamic and precisely organized process during which one or more baby develops. Embryonic development relies on the formation of the placenta, allowing nutrient and oxygen exchange between the mother and the fetus. Dysfunction of placental formation lead to pregnancy disorders such as preeclampsia (PE) with serious deleterious consequences for fetal and maternal health. Identifying factors involved in fetoplacental homeostasis could inform better diagnostic and therapeutic strategies for these pathological pregnancies. Here, we summarize actions of elabela, apelin and their common receptor APJ in the fetoplacental unit. Studies indicate that elabela is crucial for embryo cardiovascular system formation and early placental development, while apelin acts in mid/late gestation to modulate fetal angiogenesis and energy homeostasis. Most of these findings, drawn from animal models, indicate a key role of elabela/apelin-APJ system in the fetoplacental unit. This review also provides an overview of clinical studies investigating elabela/apelin-APJ system in pathological complicated pregnancies such as PE and gestational diabetes mellitus (GDM). While elabela-deficient mice display all the features of PE, current clinical studies show no difference in circulating elabela levels between PE and control patients which does not support a role in PE development. Conversely, apelin levels are increased during PE, but the use of apelin as an early PE marker remains to be fully investigated.

Epidermal TRPM8 channel isoform controls the balance between keratinocyte proliferation and differentiation in a cold-dependent manner.

Deviation of the ambient temperature is one of the most ubiquitous stimuli that continuously affect mammals' skin. Although the role of the warmth receptors in epidermal homeostasis (EH) was elucidated in recent years, the mystery of the keratinocyte mild-cold sensor remains unsolved. Here we report the cloning and characterization of a new functional epidermal isoform of the transient receptor potential M8 (TRPM8) mild-cold receptor, dubbed epidermal TRPM8 (eTRPM8), which is localized in the keratinocyte endoplasmic reticulum membrane and controls mitochondrial Ca(2+) concentration ([Ca(2+)]m). In turn, [Ca(2+)]m modulates ATP and superoxide (O2(·-)) synthesis in a cold-dependent manner. We report that this fine tuning of ATP and O2(·-) levels by cooling controls the balance between keratinocyte proliferation and differentiation. Finally, to ascertain eTRPM8's role in EH in vivo we developed a new functional knockout mouse strain by deleting the pore domain of TRPM8 and demonstrated that eTRPM8 knockout impairs adaptation of the epidermis to low temperatures.

Photodynamic therapy of ovarian cancer peritoneal metastasis with hexaminolevulinate: a toxicity study.

CONTEXT: While photodynamic therapy (PDT) is a promising treatment for peritoneal carcinomatosis, its use is often limited because of the toxicity of photosensitizers. In this study, safety of PDT with hexaminoevulinate (HAL), a second generation photosensitizer, is assessed. METHODS: PDT of the peritoneal cavity was performed in a rat model of peritoneal carcinomatosis. Rats were treated according to different protocols: with full or half HAL dose, after intraperitoneal or oral administration of HAL, 4 or 8h after its injection, using red or green light, after protection of the liver or cooling of the abdominal wall. Toxicity was assessed by blood tests quantifying hematocrit, liver and muscular enzymes and by pathological examination of abdominal and intrathoracic organs after treatment. The results were analyzed in the light of quantification of fluorescence and protoporphyrin IX (PPIX) content of the same organs. RESULTS: PDT with HAL induced rhabdomyolysis, intestinal necrosis and liver function test anomalies, leading to death in 2 out of 34 rats. The liver and the intestine contained high levels of PPIX (3-5 times more than tumor nodules). CONCLUSION: HAL PDT lacked specificity. However, the strategy associating diagnosis, treatment and evaluation of the results in one single procedure was effective and should be tested with other photosensitizers.

New design of textile light diffusers for photodynamic therapy.

A homogeneous and reproducible fluence delivery rate during clinical photodynamic therapy (PDT) plays a determinant role in preventing under- or overtreatment. PDT applied in dermatology has been carried out with a wide variety of light sources delivering a broad range of more or less adapted light doses. Due to the complexities of the human anatomy, these light sources do not in fact deliver a uniform light distribution to the skin. Therefore, the development of flexible light sources would considerably improve the homogeneity of light delivery. The integration of plastic optical fiber (POF) into textile structures could offer an interesting alternative. In this article, a textile light diffuser (TLD) has been developed using POF and Polyester yarns. Predetermined POF macrobending leads to side emission of light when the critical angle is exceeded. Therefore, a specific pattern based on different satin weaves has been developed in order to improve light emission homogeneity and to correct the decrease of side emitted radiation intensity along POF. The prototyped fabrics (approximately 100 cm(2): 5×20 cm) were woven using a hand loom, then both ends of the POF were coupled to a laser diode (5 W, 635 nm). The fluence rate (mW/ cm(2)) and the homogeneity of light delivery by the TLD were evaluated. Temperature evolution, as a function of time, was controlled with an infrared thermographic camera. When using a power source of 5 W, the fluence rate of the TLD was 18±2.5 mw/cm(2). Due to the high efficiency of the TLD, the optical losses were very low. The TLD temperature elevation was 0.6 °C after 10 min of illumination. Our TLD meets the basic requirements for PDT: homogeneous light distribution and flexibility. It also proves that large (500 cm(2)) textile light diffusers adapted to skin, but also to peritoneal or pleural cavity, PDTs can be easily produced by textile manufacturing processes.

Prenatal fasudil exposure alleviates fetal growth but programs hyperphagia and overweight in the adult male rat.

Numerous data indicate that Rho kinase inhibitors, such as Fasudil, may constitute a novel therapy for cardiovascular and metabolic diseases. We evaluated long-term effects of exposure to Fasudil during late gestation (10 mg/day) in male rat offspring from birth until 9 months. We also analyzed its effects in offspring from hypertensive mothers treated with a nitric oxide synthesis inhibitor (L-NAME; 50 mg/day). Prenatal exposure to Fasudil did not affect birth weight, but increased body weight from postnatal day 7 (P7) to 9 months. In intrauterine growth-restricted (IUGR) fetuses exposed to L-NAME, maternal Fasudil treatment increased birth weight. At P42 and P180, rats exposed to Fasudil and L-NAME showed alterations of their food intake as well as an increased basal glycemia associated with mild glucose intolerance at 6 months which was also observed in Fasudil-exposed rats. In 9 month-old rats, exposure to Fasudil increased the daily food intake as well as hypothalamic mRNA level of the orexigenic NPY peptide without modulation of the anorexigenic POMC gene expression. Altogether, our data suggest that prenatal Fasudil exposure alleviates fetal growth in IUGR rats, but programs long-term metabolic disturbances including transient perturbations of glucose metabolism, a persistent increase of body weight gain, hyperphagia and an augmented expression of hypothalamic NPY orexigenic gene. We postulate that Fasudil treatment during perinatal periods may predispose individuals to the development of metabolic disorders.

Development of a new illumination procedure for photodynamic therapy of the abdominal cavity.

A homogeneous illumination of intra-abdominal organs is essential for successful photodynamic therapy of the abdominal cavity. Considering the current lack of outstanding light-delivery systems, a new illumination procedure was assessed. A rat model of peritoneal carcinomatosis was used. Four hours after intraperitoneal injection of hexaminolevulinate, a square illuminating panel connected to a 635-nm laser source was inserted vertically into the abdominal cavity. The abdominal incision was sutured and a pneumoperitoneum created prior to illumination. Light dosimetry was based on the calculation of the peritoneal surface by MRI. The rats were treated with a light dose of 20, 10, 5 or 2.5 J/cm(2) administered continuously with an irradiance of 7 mW/cm(2). The homogeneity of the cavity illumination was assessed by quantification of the photobleaching of the tumor lesions according to their localization and by scoring of that of the liver and of the bowel immediately after treatment. Photobleaching quantification for tumor lesions relied on the calculation of the fluorescence intensity ratio (after/before treatment) after recording of the lesions during blue-light laparoscopy and determination of their fluorescence intensity with Sigmascan Pro software. The procedure led to a homogeneous treatment of the abdominal cavity. No statistical difference was observed for the photobleaching values according to the localization of the lesions on the peritoneum (p=0.59) and photobleaching of the liver and of the intestine was homogeneous. We conclude that this procedure can successfully treat the major sites involved in peritoneal carcinomatosis.

The PACAP-regulated gene selenoprotein T is highly induced in nervous, endocrine, and metabolic tissues during ontogenetic and regenerative processes.

Selenoproteins contain the essential trace element selenium whose deficiency leads to major disorders including cancer, male reproductive system failure, or autoimmune thyroid disease. Up to now, 25 selenoprotein-encoding genes were identified in mammals, but the spatiotemporal distribution, regulation, and function of some of these selenium-containing proteins remain poorly documented. Here, we found that selenoprotein T (SelT), a new thioredoxin-like protein, is regulated by the trophic neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) in differentiating but not mature adrenomedullary cells. In fact, our analysis revealed that, in rat, SelT is highly expressed in most embryonic structures, and then its levels decreased progressively as these organs develop, to vanish in most adult tissues. In the brain, SelT was abundantly expressed in neural progenitors in various regions such as the cortex and cerebellum but was undetectable in adult nervous cells except rostral migratory-stream astrocytes and Bergmann cells. In contrast, SelT expression was maintained in several adult endocrine tissues such as pituitary, thyroid, or testis. In the pituitary gland, SelT was found in secretory cells of the anterior lobe, whereas in the testis, the selenoprotein was present only in spermatogenic and Leydig cells. Finally, we found that SelT expression is strongly stimulated in liver cells during the regenerative process that occurs after partial hepatectomy. Taken together, these data show that SelT induction is associated with ontogenesis, tissue maturation, and regenerative mechanisms, indicating that this PACAP-regulated selenoprotein may play a crucial role in cell growth and activity in nervous, endocrine, and metabolic tissues.

Maternal prenatal undernutrition alters the response of POMC neurons to energy status variation in adult male rat offspring.

Epidemiological studies suggest that maternal undernutrition predisposes the offspring to development of energy balance metabolic pathologies in adulthood. Using a model of a prenatal maternal 70% food-restricted diet (FR30) in rats, we evaluated peripheral parameters involved in nutritional regulation, as well as the hypothalamic appetite-regulatory system, in nonfasted and 48-h-fasted adult offspring. Despite comparable glycemia in both groups, mild glucose intolerance, with a defect in glucose-induced insulin secretion, was observed in FR30 animals. They also exhibited hyperleptinemia, despite similar visible fat deposits. Using semiquantitative RT-PCR, we observed no basal difference of hypothalamic proopiomelanocortin (POMC) and neuropeptide Y (NPY) gene expression, but a decrease of the OB-Rb and an increase of insulin receptor mRNA levels, in FR30 animals. These animals also exhibited basal hypercorticosteronemia and a blunted increase of corticosterone in fasted compared with control animals. After fasting, FR30 animals showed no marked reduction of POMC mRNA levels or intensity of beta-endorphin-immunoreactive fiber projections. By contrast, NPY gene expression and immunoreactive fiber intensity increased. FR30 rats also displayed subtle alterations of food intake: body weight-related food intake was higher and light-dark phase rhythm and refeeding time course were modified after fasting. At rest, in the morning, hyperinsulinemia and a striking increase in the number of c-Fos-containing cells in the arcuate nucleus were observed. About 30% of the c-Fos-expressing cells were POMC neurons. Our data suggest that maternal undernutrition differently programs the long-term appetite-regulatory system of offspring, especially the response of POMC neurons to energy status and food intake rhythm.

Selenoprotein T is a PACAP-regulated gene involved in intracellular Ca2+ mobilization and neuroendocrine secretion.

Selenoproteins contain the essential trace element selenium, the deficiency of which is associated with cancer or accelerated aging. Although selenoproteins are thought to be instrumental for the effects of selenium, the biological function of many of these proteins remains unknown. Here, we studied the role of selenoprotein T (SelT), a selenocysteine (Sec) -containing protein with no known function, which we have identified as a novel target gene of the neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) during PC12 cell differentiation. SelT was found to be ubiquitously expressed throughout embryonic development and in adulthood in rat. Immunocytochemical analysis revealed that SelT is mainly localized to the endoplasmic reticulum through a hydrophobic domain. PACAP and cAMP induced a rapid and long-lasting increase in SelT gene expression in PC12 cells, in a Ca(2+)-dependent manner. These results suggested a possible role of SelT in PACAP signaling during PC12 cell differentiation. Indeed, overexpression of SelT in PC12 cells provoked an increase in the concentration of intracellular Ca(2+) ([Ca(2+)](i)) that was dependent on the Sec residue. Conversely, SelT gene knockdown inhibited the PACAP-induced increase in [Ca(2+)](i) and reduced hormone secretion. These findings demonstrate the implication of a selenoprotein in the regulation of Ca(2+) homeostasis and neuroendocrine secretion in response to a cAMP-stimulating trophic factor.

Evaluation of BCECF fluorescence ratio imaging to properly measure gastric intramucosal pH variations in vivo.

Our purpose is to evaluate intramucosal gastric pH video imaging by 2('),7(')-bis(carboxyethyl)-5,6-carboxyfluorescein (BCECF) fluorescence ratio techniques. We use a video endoscopic imaging system and BCECF as the pH fluorescent probe. Systemic in vivo pH variations are studied in 10 pigs: five in the control group and five with respiratory acidosis induced through rebreathing. The intramucosal pH of the gastric wall is measured every 5 s and the results demonstrate a good correlation (pearson correlation=0.832) between blood gases pH measurements and pH measured with the video endocopic imaging system. Our results confirm the feasibility of using BCECF fluorescence pH imaging to measure intramucosal pH in vivo.

Altered hypothalamo-pituitary-adrenal and sympatho-adrenomedullary activities in rats bred for high anxiety: central and peripheral correlates.

Wistar rats have been selectively bred for high (HABs) or low (LABs) anxiety-related behavior based on results obtained in the elevated-plus maze. They also display robust behavioral differences in a variety of additional anxiety tests. The present study was undertaken to further characterize physiological substrates that contribute to the expression of this anxious trait. We report changes in brain and peripheral structures involved in the regulation of both the hypothalamo-pituitary-adrenal (HPA) and sympatho-adrenal systems. Following exposure to a mild stressor, HABs displayed a hyper-reactivity of the HPA axis associated with a hypo-reactivity of the sympatho-adrenal system and a lower serotonin turnover in the lateral septum and amygdala. At rest, HABs showed a higher adrenal weight and lower tyrosine hydroxylase and phenylethanolamine-N-methyltransferase mRNAs expression in their adrenals than LABs. In the anterior pituitary, HABs also exhibited increased proopiomelanocortin and decreased vasopressin V1b receptor mRNAs expression, whereas glucocorticoid receptor mRNA levels remained unchanged. These results indicate that the behavioral phenotype of HABs is associated with peripheral and central alterations of endocrine mechanisms involved in stress response regulation. Data are discussed in relation to coping strategies adopted to manage stressful situations. In conclusion, HABs can be considered as an useful model to study the etiology and pathophysiology of stress-related disorders and their neuroendocrine substrates.

Dynamics of temperature dependent modifications of blood in the near-infrared.

BACKGROUND AND OBJECTIVES: Laser irradiation induces blood coagulation by heating of blood components. It is a complex phenomenon which encompasses a variety of processes, such as cell shape modification, cell membrane rupture, protein denaturation, aggregation, and finally blood gelation. An in vitro study was performed to investigate heating temperatures leading to transformation of blood and to have a better understanding of the dynamics of temperature dependent modifications of blood in the near-infrared. STUDY DESIGN/MATERIALS AND METHODS: Slow heating of whole blood and hemolized blood was performed using a specific optical chamber. Eight hundred and five and 940 nm light transmission of blood was measured as a function of time during heating at various temperatures (60-75 degrees C). RESULTS: During heating of whole blood, three phases were clearly identified. For hemolized blood, only phase 3 was present. For whole blood, the duration of each phase was correlated to blood temperature. A temporary increase of transmission was observed during heating with a maximum at 65 degrees C. The analysis of the dynamics of temperature dependent modifications of blood are consistent with cell shape modification, denaturation, and aggregation of blood, resulting in the formation of an aqueous gel-matrix. CONCLUSIONS: "Slow" vessel heating which is now proposed as the optimal mechanism for permanent vessel closure should be reconsidered in terms of our results. In that particular case, the optical coefficients of blood could be different from those expected. In case of a large blood vessel, this could be an advantage since a "temporary" higher transmission of light could lead to a more homogeneous heating of the blood vessel. In case of a small blood vessel, this phenomenon could lead to a collateral damage of the skin.

Prenatal morphine exposure affects sympathoadrenal axis activity and serotonin metabolism in adult male rats both under basal conditions and after an ether inhalation stress.

We have previously shown that prenatal morphine exposure inhibited the hypothalamo-pituitary-adrenal (HPA) axis and altered the hypothalamic metabolism of serotonin during the early postnatal period in the rat and induced a chronic sympathoadrenal hyperactivity under resting conditions in adult male rats. In this study, we examined the effects of prenatal morphine exposure on the responsiveness to an acute ether inhalation stress of the sympathoadrenal and HPA axis and the hippocampal and hypothalamic concentrations of serotonin (5HT) and 5-hydroxylindoleacetic acid (5HIAA) in 3-month-old male rats. The plasma levels of adrenocorticopic hormone (ACTH) and corticosterone (B) did not differ between the two groups both under resting conditions and after ether exposure. Ether inhalation increased adrenal tyrosine hydroxylase (TH) and phenylethanolamine N-methyltransferase (PNMT) mRNA expression as well as adrenal epinephrine (E) concentration in control rats but not in prenatally morphine-exposed (PM) animals. Under basal conditions, hypothalamic concentrations of 5HT and 5HIAA increased in PM animals. In contrast to control animals, PM rats showed, in response to stress, an increased level of 5HT and 5HIAA in both the hypothalamus and in the hippocampus. In conclusion, prenatal morphine exposure produces long-lasting alterations in brain serotonin transmission and in the sympathoadrenal responsiveness to an acute systemic stress.

Perinatal food deprivation induces marked alterations of the hypothalamo-pituitary-adrenal axis in 8-month-old male rats both under basal conditions and after a dehydration period.

Dehydration is a classic homeostatic stressor in rats that leads to a series of endocrine responses including stimulation of the hypothalamo-pituitary-adrenal (HPA) axis. During the last decade, it has been well established that perinatal food restriction is associated with the onset of diseases in adults. Our previous demonstration of long-term alterations in HPA axis activity in both basal conditions and after a 72-hour dehydration period in 4-month-old rats exposed to a 50% maternal food restriction (FR50) in late gestation and lactation prompted us to investigate whether such perinatal undernutrition further affects HPA axis activity in mature animals. As previously described in 4-month-old rats under basal conditions, 8-month-old FR50 rats showed reduced body weight and an enhanced ratio between mineralocorticoid receptor (MR) and glucocorticoid receptor (GR) mRNA levels in the hippocampus, as well as increased pro-opiomelanocortin (POMC) mRNA levels in the adenohypophysis. In addition, numerous additional alterations appeared in mature rats. In the hypothalamus, levels of vasopressin (VP) mRNAs were increased both in the paraventricular nucleus (PVN) and in the supraoptic nucleus (SON). In the adenohypophysis, GR and prohormone-convertase 2 (PC2) mRNA levels were significantly increased, whereas prohormone-convertase 1 (PC1) mRNA was not affected by maternal undernutrition. Interestingly, undernourished animals exhibited high plasma levels of total and free corticosterone in spite of normal corticotropin (ACTH) levels, an indication that HPA basal activity is enhanced by maternal undernutrition in 8-month-old animals. Dehydration for 72 h induced a rise in ACTH plasma levels, but did not modify total and free corticosterone plasma levels in 8-month-old FR50 animals. In the adenopituitary, POMC mRNA levels were decreased after dehydration but PC1 mRNA levels were unaffected. The present study indicates that maternal food restriction during the perinatal period dramatically affects the activity of the HPA axis until the age of 8 months. We speculate that higher basal HPA activity and an inadequate HPA response after dehydration in mature animals may contribute to diseases such as hypertension, known to develop with aging in perinatally growth-restricted rats.

Altered control of the hypothalamo-pituitary-adrenal axis in adult male rats exposed perinatally to food deprivation and/or dehydration.

Dehydration, a classic homeostatic stressor in rats, leads to a series of well characterized endocrine responses including stimulation of the hypothalamo-pituitary-adrenal (HPA) axis. In this study, the hypothesis to be tested was that a 50% maternal food restriction (FR50) in late gestation and lactation may have long-term repercussions on HPA axis responsiveness to dehydration in offspring. For this purpose, we studied HPA axis activity in 4-month-old control (C) and perinatally malnourished male rats after a 72-hour water deprivation period. Furthermore, we investigated the long-lasting effects of perinatal maternal malnutrition on the basal activity of the HPA axis. Under basal conditions, rats exposed to perinatal malnutrition showed reduced body weight, enhanced mineralocorticoid receptor (MR) mRNA levels in CA2 and CA3 hippocampal areas, but decreased glucocorticoid receptor (GR) mRNA levels in CA1, CA3 and dentate gyrus (DG) areas. In contrast, the levels of corticotropin-releasing hormone (CRH) and vasopressin (VP) mRNAs in the hypothalamic paraventricular nucleus (PVN) as well as of VP mRNA in the supraoptic nucleus (SON) were unaffected by maternal undernutrition. Expression of proopiomelanocortin (POMC) in the adenohypophysis was significantly enhanced, whereas prohormone convertase-1 (PC1) was not affected. Perinatal malnutrition reduced absolute adrenal weight but did not affect circulating levels of adrenocorticotropin (ACTH), corticosterone and free corticosterone as well as corticosteroid-binding globulin (CBG) binding capacity. Seventy-two hours of dehydration induced a decrease in body weight and CRH mRNA levels in PVN of controls as well as of FR50 rats, but also led to a rise in plasma corticosterone and free corticosterone without changing CBG binding capacity. Dehydration also induced an increase in adenopituitary POMC (C) and PC1 (FR50), PVN and SON VP (C) and GR in CA1 hippocampal area (FR50) mRNA levels and plasma ACTH (C), but a decrease in MR in DG (C) and GR in CA3 and DG (C) mRNA levels. We conclude that maternal food restriction during the perinatal period affects (1) the adult basal activity of the HPA axis with mainly opposite effects on hippocampal MR and GR gene expression and an increase in adenopituitary POMC gene expression, and (2) the responsiveness to water deprivation in adults. In the latter case, the rise in plasma ACTH levels, adenopituitary POMC gene expression, hypothalamic VP gene expression, and the decrease in hippocampal MR gene expression in DG and GR gene expression in CA3 and DG observed in controls are lacking in FR50 rats. In contrast, drastic adenopituitary PC1 gene expression occurred in FR50 rats but not in control animals.

Perinatal maternal food restriction induces alterations in hypothalamo-pituitary-adrenal axis activity and in plasma corticosterone-binding globulin capacity of weaning rat pups.

We investigated the effects of perinatal maternal malnutrition on the hypothalamo-pituitary-adrenal (HPA) axis activity in both basal and stressful conditions in newborn rats at weaning. Mothers from the control group were fed ad libitum. Mothers exposed to food restriction received 50% (FR50) of the daily intake of pregnant dams during the last week of gestation (Pre group), lactation (Post group) or both periods (PP group) in order to compare the long-term effects of gestational and/or lactational restriction. FR50 reduced the body growth of pups from the Post and PP groups as soon as day 11 until day 21 after birth. At weaning, pups of the Post and PP groups showed reduced adrenal, thymus and liver weights. Although the plasma adrenocorticotropic hormone (ACTH) level was reduced in pups, FR50 affected neither corticotropin-releasing hormone expression and peptide synthesis in the hypothalamus nor proopiomelanocortin expression in the adenohypophysis. Basal circulating levels of corticosterone were not markedly affected by FR50, but free corticosterone concentration was increased in the PP group. Plasma corticosterone-binding globulin (CBG) was decreased in newborns from both the Post and PP groups. Mineralocorticoid receptor gene expression was significantly increased in both CA1 and CA3 hippocampal areas in the PP group. Glucocorticoid receptor gene expression was increased in CA1, CA2 and dentate gyrus hippocampal areas in the Pre group, as well as in CA1, CA3 and DG areas in the Post group. The ether inhalation-induced plasma ACTH increase was weaker in pups from the Post and PP groups. Similarly, the ether inhalation-induced plasma corticosterone increase returned to basal levels in the Post group, or to weaker values than baseline in the PP group 90 min after this stressful procedure. The present work suggests that maternal food restriction during the perinatal period (gestation and lactation) or during lactation only reduces the postnatal somatic growth of pups and disturbs the activity of the HPA axis at weaning under both resting and stress conditions. A reduction in the plasma CBG-binding capacity, associated with a probable increase in hippocampal corticosteroid receptors, could reinforce glucocorticoid-mediated negative feedback and shorten stress-induced activation of the HPA axis in pups at weaning.