Preterm birth is currently the most important problem in maternal-child health in the United States. Epidemiological studies have suggested that two factors, maternal stress and maternal urogenital tract infection, are significantly and independently associated with an increased risk of spontaneous preterm birth. These factors are also more prevalent in the population of sociodemographically disadvantaged women who are at increased risk for preterm birth. Studies of the physiology of parturition suggest that neuroendocrine and immune processes play important roles in the physiology and pathophysiology of normal and preterm parturition. However, not all women with high levels of stress and/or infection deliver preterm, and little is understood about factors that modulate susceptibility to pathophysiological events of the endocrine and immune systems in pregnancy. We present here a comprehensive, biobehavioural model of maternal stress and spontaneous preterm delivery. According to this model, chronic maternal stress is a significant and independent risk factor for preterm birth. The effects of maternal stress on preterm birth may be mediated through biological and/or behavioural mechanisms. We propose that maternal stress may act via one or both of two physiological pathways: (a) a neuroendocrine pathway, wherein maternal stress may ultimately result in premature and/or greater degree of activation of the maternal-placental-fetal endocrine systems that promote parturition; and (b) an immune/inflammatory pathway, wherein maternal stress may modulate characteristics of systemic and local (placental-decidual) immunity to increase susceptibility to intrauterine and fetal infectious-inflammatory processes and thereby promote parturition through pro-inflammatory mechanisms. We suggest that placental corticotropin-releasing hormone may play a key role in orchestrating the effects of endocrine and inflammatory/immune processes on preterm birth. Moreover, because neuroendocrine and immune processes extensively cross-regulate one another, we further posit that exposure to both high levels of chronic stress and infectious pathogens in pregnancy may produce an interaction and multiplicative effect in terms of their combined risk for preterm birth. Finally, we hypothesise that the effects of maternal stress are modulated by the nature, duration and timing of occurrence of stress during gestation. A discussion of the components of this model, including a theoretical rationale and review of the available empirical evidence, is presented. A major strength of this biobehavioural perspective is the ability to explore new questions and to do so in a manner that is more comprehensive than has been previously attempted. We expect findings from this line of proposed research to improve our present state of knowledge about obstetric risk assessment for preterm birth by determining the characteristics of pregnant women who are especially susceptible to stress and/or infection, and to broaden our understanding of biological (endocrine, immune, and endocrine-immune interactions) mechanisms that may translate social adversity during pregnancy into pathophysiology, thereby suggesting intervention strategies.

We have recently found that susceptibility to streptococcal cell wall (SCW)-induced arthritis in Lewis (LEW/N) rats is due, in part, to defective inflammatory and stress mediator-induced activation of the hypothalamic-pituitary-adrenal (HPA) axis. Conversely, the relative arthritis resistance of histocompatible Fischer (F344/N) rats is related to their intact responses to the same stimuli. Specifically, LEW/N rats, in contrast to F344/N rats, have markedly impaired plasma corticotropin and corticosterone responses to SCW, recombinant human interleukin 1 alpha, the serotonin agonist quipazine, or synthetic rat/human corticotropin-releasing hormone (CRH). To explore the mechanism of this defect, we examined the functional integrity of the hypothalamic CRH neuron in LEW/N rats compared to F344/N rats. LEW/N rats, in contrast to F344/N rats, showed profoundly deficient paraventricular nucleus CRH mRNA levels and hypothalamic CRH content in response to SCW. Compared to F344/N rats, there was no increase in LEW/N hypothalamic CRH content or CRH release from explanted LEW/N hypothalami in organ culture in response to recombinant interleukin 1 alpha. These data provide strong evidence that the defective LEW/N corticotropin and corticosterone responses to inflammatory and other stress mediators, and the LEW/N susceptibility to experimental arthritis, are due in part to a hypothalamic defect in the synthesis and secretion of CRH. The additional finding of deficient expression in LEW/N rats of the hypothalamic enkephalin gene, which is coordinately regulated with the CRH gene in response to stress, suggests that the primary defect is not in the CRH gene but is instead related to its inappropriate regulation.

There is compelling evidence that impaired corticosteroid receptor function is the key mechanism in the pathogenesis of depression resulting in a dysfunctional stress hormone regulation, which can be most sensitively detected with the combined dexamethasone (dex)/corticotropin releasing hormone (CRH) test. Treatment with different kinds of antidepressants is associated with a reduction of the hormonal responses to the combined dex/CRH test suggesting normalization of impaired corticosteroid receptor signaling as the final common pathway of these drugs. Consequently, the combined dex/CRH test is suggested as a screening tool to decide whether new compounds designed as antidepressants provide sufficient efficacy to normalize corticoid receptor signaling in depressed patients. We summarize own data and findings from the literature suggesting that (1) the neuroendocrine response to the combined dex/CRH test is elevated during a major depressive episode, but (2) tends to normalize after successful treatment. (3) Favorable response to antidepressant treatment can be predicted by determining the dex suppresser status on admission. For optimal prediction of non-response to antidepressant treatment, however, the results of a second dex/CRH test are necessary. These findings, together with the fact that impaired corticosteroid receptor signaling is considered as key mechanism of the pathogenesis in depression, support the suitability of the combined dex/CHR test as a surrogate marker for treatment response in depression. In conclusion, the combined dex/CRH test is a promising candidate to serve as a screening tool for the antidepressive effects of new compounds in clinical drug trials. Furthermore, the test appears to be capable of predicting the individual likelihood to respond to a current antidepressant treatment. If a drug treatment fails to normalize the outcome of the combined dex/CRH test, a change of the treatment strategy is recommended. Further systematic research is required and already ongoing to confirm the suitability of the combined dex/CRH test as a surrogate marker in depression.

Several inflammatory skin conditions, including atopic dermatitis (AD) and psoriasis, are exacerbated by stress. Recent evidence suggests that crosstalk between mast cells, neurons and keratinocytes might be involved in such exacerbation. Mast cells are distributed widely in the skin, are present in increased numbers in AD and are located in close proximity to substance P- or neurotensin-containing neurons. Corticotropin-releasing factor (CRF), its structurally related peptide urocortin (Ucn) and their receptors are also present in the skin and their levels are increased following stress. Human mast cells synthesize and secrete both CRF and Ucn in response to immunoglobulin E receptor (FcepsilonRI) crosslinking. Mast cells also express CRF receptors, activation of which leads to the selective release of cytokines and other pro-inflammatory mediators. Thus, we propose that CRF receptor antagonists could be used together with natural molecules, such as retinol and flavonoids, to inhibit mast cell activation and provide new therapeutic options for chronic inflammatory conditions exacerbated by stress.

BACKGROUND

The Hsp90 cochaperone FK506 binding protein 5 (FKBP5) is an established regulator of the glucocorticoid receptor (GR), and numerous genetic studies have linked it to stress-related diseases such as major depression or posttraumatic stress disorder. However, translational studies including genetic animal models are lacking.

METHODS

Mice deficient of FKBP5 were generated and analyzed in comparison with wildtype littermates. They were subjected to several test paradigms characterizing their emotionality, stress reactivity, and coping behavior as well as hypothalamus-pituitary-adrenal axis function and regulation. Moreover, protein expression of GR and FKBP5 was determined in different brain structures 8 days after stress exposure. The combined dexamethasone/corticotropin-releasing hormone test was performed both in mice and healthy human subjects of different FKBP5 genotypes. The GR function was evaluated by reporter gene assays.

RESULTS

Under basal conditions, deletion of FKBP5 did not change exploratory drive, locomotor activity, anxiety-related behavior, stress-coping, or depression-like behavior. After exposure to different acute stressors of sufficient intensity, however, it led to a more active coping behavior. Moreover, loss of FKBP5 decreased hypothalamus-pituitary-adrenal axis reactivity and GR expression changes in response to stressors. In mice and humans, the FKBP5 genotype also determined the outcome of the dexamethasone/corticotropin-releasing hormone test.

CONCLUSIONS

This study in mice and humans presents FKBP5 as a decisive factor for the physiological stress response, shaping neuroendocrine reactivity as well as coping behavior. This lends strong support to the concept emerging from human studies of FKBP5 as important factor governing gene-environment interactions relevant for the etiology of affective disorders.

OBJECTIVE

Genome-wide investigations provide systematic information regarding the neurobiology of psychiatric disorders.

OBJECTIVE

To identify biological pathways that contribute to risk for bipolar disorder (BP) using genes with consistent evidence for association in multiple genome-wide association studies (GWAS).

METHODS

Four independent data sets with individual genome-wide data available in July 2011 along with all data sets contributed to the Psychiatric Genomics Consortium Bipolar Group by May 2012. A prior meta-analysis was used as a source for brain gene expression data.

METHODS

The 4 published GWAS were included in the initial sample. All independent BP data sets providing genome-wide data in the Psychiatric Genomics Consortium were included as a replication sample.

METHODS

We identified 966 genes that contained 2 or more variants associated with BP at P < .05 in 3 of 4 GWAS data sets (n = 12,127 [5253 cases, 6874 controls]). Simulations using 10,000 replicates of these data sets corrected for gene size and allowed the calculation of an empirical P value for each gene; empirically significant genes were entered into a pathway analysis. Each of these pathways was then tested in the replication sample (n = 8396 [3507 cases, 4889 controls]) using gene set enrichment analysis for single-nucleotide polymorphisms. The 226 genes were also compared with results from a meta-analysis of gene expression in the dorsolateral prefrontal cortex.

METHODS

Empirically significant genes and biological pathways. RESULTS Among 966 genes, 226 were empirically significant (P < .05). Seventeen pathways were overrepresented in analyses of the initial data set. Six of the 17 pathways were associated with BP in both the initial and replication samples: corticotropin-releasing hormone signaling, cardiac β-adrenergic signaling, phospholipase C signaling, glutamate receptor signaling, endothelin 1 signaling, and cardiac hypertrophy signaling. Among the 226 genes, 9 differed in expression in the dorsolateral prefrontal cortex in patients with BP: CACNA1C, DTNA, FOXP1, GNG2, ITPR2, LSAMP, NPAS3, NCOA2, and NTRK3.

CONCLUSIONS

Pathways involved in the genetic predisposition to BP include hormonal regulation, calcium channels, second messenger systems, and glutamate signaling. Gene expression studies implicate neuronal development pathways as well. These results tend to reinforce specific hypotheses regarding BP neurobiology and may provide clues for new approaches to treatment and prevention.

Individual variations in hypothalamic-pituitary-adrenal (HPA) function are most evident at or beyond the time of puberty, when marked changes in sex steroid release occur. To explore the nature by which gender differences in HPA function emerge we examined in prepubertal (approximately 30-d-old) and postpubertal (approximately 60-d-old) male and female rats HPA activity under basal conditions and in response to 30 min of restraint. Within the ACTH-regulating, medial parvocellular portion of the paraventricular nucleus, restraint-induced Fos protein and arginine vasopressin heteronuclear RNA were lower in 60- than in 30-d-old males. No such age-related shift in the response of these synaptic and transcriptional markers of cellular activation occurred in female rats. Basal CRH mRNA expression levels in the paraventricular nucleus increased with age in female but not male rats. Conversely, only male rats showed an age-related increase in basal CRH mRNA in the central amygdala, suggesting that neuronal and neurosecretory CRH-expressing cell types are subject to different pubertal and gender influences. We conclude that gonadal regulation of the HPA axis develops via distinct mechanisms in males and females. Puberty-related shifts in parvocellular neurosecretory function in males are emphasized by stress-induced shifts in neuronal activation, whereas biosynthetic alterations dominate in female rats.

In human addicts, drug relapse and craving are often provoked by stress. Since 1995, this clinical scenario has been studied using a rat model of stress-induced reinstatement of drug seeking. Here, we first discuss the generality of stress-induced reinstatement to different drugs of abuse, different stressors, and different behavioral procedures. We also discuss neuropharmacological mechanisms, and brain areas and circuits controlling stress-induced reinstatement of drug seeking. We conclude by discussing results from translational human laboratory studies and clinical trials that were inspired by results from rat studies on stress-induced reinstatement. Our main conclusions are (1) The phenomenon of stress-induced reinstatement, first shown with an intermittent footshock stressor in rats trained to self-administer heroin, generalizes to other abused drugs, including cocaine, methamphetamine, nicotine, and alcohol, and is also observed in the conditioned place preference model in rats and mice. This phenomenon, however, is stressor specific and not all stressors induce reinstatement of drug seeking. (2) Neuropharmacological studies indicate the involvement of corticotropin-releasing factor (CRF), noradrenaline, dopamine, glutamate, kappa/dynorphin, and several other peptide and neurotransmitter systems in stress-induced reinstatement. Neuropharmacology and circuitry studies indicate the involvement of CRF and noradrenaline transmission in bed nucleus of stria terminalis and central amygdala, and dopamine, CRF, kappa/dynorphin, and glutamate transmission in other components of the mesocorticolimbic dopamine system (ventral tegmental area, medial prefrontal cortex, orbitofrontal cortex, and nucleus accumbens). (3) Translational human laboratory studies and a recent clinical trial study show the efficacy of alpha-2 adrenoceptor agonists in decreasing stress-induced drug craving and stress-induced initial heroin lapse.

BACKGROUND

The diagnostic value of tests for detecting hypothalamic-pituitary adrenal insufficiency (HPAI) is controversial.

OBJECTIVE

Our objective was to compare standard-dose and low-dose corticotropin tests for diagnosing HPAI.

METHODS

We searched the PubMed database from 1966-2006 for studies reporting diagnostic value of standard-dose or low-dose corticotropin tests, with patient-level data obtained from original investigators.

METHODS

Eligible studies had more than 10 patients. All subjects were evaluated because of suspicion for chronic HPAI, and patient-level data were available. We excluded studies with no accepted reference standard for HPAI (insulin hypoglycemia or metyrapone test) if test subjects were in the intensive care unit or if only normal healthy subjects were used as controls.

METHODS

We constructed receiver operator characteristic (ROC) curves using patient-level data from each study and then merged results to create summary ROC curves, adjusting for study size and cortisol assay method. Diagnostic value of tests was measured by calculating area under the ROC curve (AUC) and likelihood ratios.

RESULTS

Patient-level data from 13 of 23 studies (57%; 679 subjects) were included in the metaanalysis. The AUC were as follows: low-dose corticotropin test, 0.92 (95% confidence interval 0.89-0.94), and standard-dose corticotropin test, 0.79 (95% confidence interval 0.74-0.84). Among patients with paired data (seven studies, 254 subjects), diagnostic value of low-dose corticotropin test was superior to standard-dose test (AUC 0.94 and 0.85, respectively; P<0.001).

CONCLUSIONS

Low-dose corticotropin test was superior to standard-dose test for diagnosing chronic HPAI, although it has technical limitations.

The paraventricular nucleus of the thalamus (PVT) is part of a group of midline and intralaminar thalamic nuclei implicated in arousal and attention. This study examined the connections between the PVT and the forebrain by using the retrograde tracer cholera toxin B (CTb) and the anterograde tracer biotin dextran amine (BDA). The anterior and posterior regions of the PVT were found to send a dense projection to the nucleus accumbens. The posterior PVT was also found to provide a strong projection to the lateral bed nucleus of the stria terminalis (BST), interstitial nucleus of the posterior limb of the anterior commissure (IPAC), and central nucleus of the amygdala (CeA), regions associated with the extended amygdala. In contrast, the anterior PVT was found to send a weaker projection to the extended amygdala. The basolateral nucleus of the amygdala and the medial prefrontal cortex were found to receive a relatively weak projection from the PVT, and other regions of the BST and amygdala were found to be poorly innervated by the PVT. In addition, the PVT was found to innervate regions in the extended amygdala that contained corticotropin-releasing factor (CRF) neurons, many of which were found to receive apparent contacts from PVT fibers. The projection from the PVT to the nucleus accumbens and extended amygdala places the PVT in a key anatomical position to influence adaptive behaviors as well as the physiological and neuroendocrine responses associated with these behaviors.

Stressors motivate an array of adaptive responses ranging from 'fight or flight' to an internal urgency signal facilitating long-term goals. However, traumatic or chronic uncontrollable stress promotes the onset of major depressive disorder, in which acute stressors lose their motivational properties and are perceived as insurmountable impediments. Consequently, stress-induced depression is a debilitating human condition characterized by an affective shift from engagement of the environment to withdrawal. An emerging neurobiological substrate of depression and associated pathology is the nucleus accumbens, a region with the capacity to mediate a diverse range of stress responses by interfacing limbic, cognitive and motor circuitry. Here we report that corticotropin-releasing factor (CRF), a neuropeptide released in response to acute stressors and other arousing environmental stimuli, acts in the nucleus accumbens of naive mice to increase dopamine release through coactivation of the receptors CRFR1 and CRFR2. Remarkably, severe-stress exposure completely abolished this effect without recovery for at least 90 days. This loss of CRF's capacity to regulate dopamine release in the nucleus accumbens is accompanied by a switch in the reaction to CRF from appetitive to aversive, indicating a diametric change in the emotional response to acute stressors. Thus, the current findings offer a biological substrate for the switch in affect which is central to stress-induced depressive disorders.

Glucocorticoids may underlie the association between prenatal stress, low birth weight and adult stress-associated disorders, e.g. hypertension and type 2 diabetes, increased hypothalamic-pituitary-adrenal (HPA) activity and affective dysfunction. Normally, 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2) rapidly inactivates glucocorticoids in placenta and many foetal tissues, thus acting as a 'barrier' to maternal steroids. We investigated the effect of inhibiting foeto-placental 11beta-HSD in rats, using carbenoxolone (CBX), on subsequent HPA activity and regulation and stress-induced behaviour in adult offspring. Pregnant Wistar rats were injected with CBX (12.5 mg s.c.) or vehicle daily throughout pregnancy. CBX treatment reduced birth weight. Adult offspring of CBX-treated dams had persistently reduced body weight, increased basal corticosterone (CORT) levels, increased corticotropin-releasing hormone (CRH) and reduced glucocorticoid receptor (GR) mRNA in the hypothalamic paraventricular nucleus, though hippocampal GR and mineralocorticoid receptor (MR) mRNA expression were unaltered. In addition, these animals showed less grooming and rearing in an open field and reduced immobility in a forced swim test, and had increased GR mRNA expression in the basolateral (BLA), central (CEA) and medial (MEA) nuclei of the amygdala, with unaltered MR mRNA. These data suggest that disturbance of the foeto-placental enzymatic barrier to maternal glucocorticoids reduces birth and body weight, and produces permanent alterations of the HPA axis and anxiety-like behaviour in aversive situations. The behavioural and HPA effects may reflect GR gene programming in amygdala and hypothalamus, respectively. Foetal overexposure to endogenous glucocorticoids (prenatal stress or reduced activity of foeto-placental 11beta-HSD) may represent a common link between the prenatal environment, foetal growth and adult neuroendocrine and affective disorders.

Corticotropin releasing factor (CRF), a key neuroregulator of the hypothalamic-pituitary-adrenal cortical axis, also displays a broad range of effects on the endocrine, central nervous and immune systems. Having recently characterized the human pituitary CRF receptor by expression cloning of cDNA from a human Cushing's corticotropic adenoma, we report here the structure of the cDNA for a rat brain CRF receptor (rCRF-R) which was cloned by hybridization from a rat brain cDNA library. The sequence of the rCRF-R encodes a 415 amino acid protein comprising seven membrane spanning domains. The rCRF-R is 97% identical at the amino acid level to the human pituitary tumor CRF receptor, differing by only 12 amino acids. When expressed in COSM6 cells, the rCRF-R binds CRF with high affinity (Kd = 1.7 (0.8-3.8)nM). The receptor transduces a CRF stimulated accumulation of intracellular cAMP which is inhibited by the CRF antagonist, alpha helCRF(9-41). These results suggest that the brain expresses a CRF receptor similar to that in the pituitary.

Recent evidence suggests that corticotropin-releasing factor (CRF) receptor (CRFR) signaling is involved in modulating binge-like ethanol consumption in C57BL/6J mice. In this report, a series of experiments were performed to further characterize the role of CRFR signaling in binge-like ethanol consumption. The role of central CRFR signaling was assessed with intracerebroventricular (i.c.v.) infusion of the nonselective CRFR antagonist, alpha-helical CRF(9-41) (0, 1, 5, 10 microg/1 microl). The contribution of central CRF type 2 receptor (CRF(2)R) signaling was assessed with i.c.v. infusion of the selective CRF(2)R agonist, urocortin (Ucn) 3 (0, 0.05, 0.1, or 0.5 microg/1 microl). The role of the hypothalamic-pituitary-adrenal (HPA) axis was assessed by pretreating mice with intraperitoneal (i.p.) injection of (1) the corticosterone synthesis inhibitor, metyrapone (0, 50, 100, 150 mg/kg) or (2) the glucocorticoid receptor antagonist, mifepristone (0, 25, 50 mg/kg), and (3) by using radioimmunoassay to determine whether binge-like ethanol intake influenced plasma corticosterone levels. Finally, we determined whether the ability of the CRF(1)R antagonist, CP-154,526 (CP; 0, 10, 15 mg/kg, i.p.), to blunt binge-like drinking required normal HPA axis signaling by comparing the effectiveness of CP in adrenalectomized (ADX) and normal mice. Results showed that i.c.v. infusion of a 1 microg dose of alpha-helical CRF(9-41) significantly attenuated binge-like ethanol consumption relative to vehicle treatment, and i.c.v. infusion of Ucn 3 dose-dependently blunted binge-like drinking. On the other hand, metyrapone nonselectively reduced both ethanol and sucrose consumption, mifepristone did not alter ethanol drinking, and binge-like drinking did not correlate with plasma corticosterone levels. Finally, i.p. injection of CP significantly attenuated binge-like ethanol intake in both ADX and normal mice. Together, these results suggest that binge-like ethanol intake in C57BL/6J mice is modulated by CRF(1)R and CRF(2)R signaling, such that blockade of CRF(1)R or activation of CRF(2)R effectively reduces excessive ethanol intake. Furthermore, normal HPA axis signaling is not necessary to achieve binge-like drinking behavior.

Hypothalamic-pituitary-adrenal (HPA) responses remain intact or increase after chronic or repeated stress despite robust levels of circulating glucocorticoids that would be expected to restrain the responsiveness of the axis. The purpose of this study was to determine whether chronic stress altered corticosteroid receptor messenger RNA (mRNA) levels at any locus known to mediate glucocorticoid feedback on HPA function (i.e. hippocampus or hypothalamus), whether such effects were glucocorticoid dependent, and whether changes in corticosteroid receptor function could potentially contribute to the putative shift from corticotropin-releasing hormone (CRH) to arginine vasopressin (AVP) in the hypothalamic paraventricular nucleus (PVN) in the modulation of pituitary adrenal function occurring during chronic stress. We compared the stress responsiveness of sham-operated rats to that of adrenalectomized rats using a moderate dose of corticosterone (CORT) pellet replacement (ADX + CORT group). Acute immobilization caused a significant increase in CRH, but not AVP, mRNA levels in the parvocellular PVN in sham rats. The ADX + CORT group showed significantly greater increases in both CRH and AVP mRNA levels in the PVN compared to sham rats. These data indicate that PVN AVP mRNA levels are more sensitive to glucocorticoid negative feedback than are the levels of CRH mRNA. In repeated stress, the sham groups showed robust increases in PVN CRH and AVP mRNA levels despite high levels of plasma CORT. The rise in AVP mRNA levels was greater than that in CRH mRNA. Type II glucocorticoid receptor mRNA in the hippocampus and PVN was decreased in the repeatedly stressed sham group. These data suggest a decrease in the CORT negative feedback restraint of PVN CRH and AVP mRNA levels repeated stress and a persistence of relatively greater responsiveness of AVP mRNA levels to CORT negative feedback. After repeated stress in ADX+CORT rats, both PVN CRH and AVP mRNA levels showed robust responses, with a relatively greater increase in AVP mRNA. These data indicate that a CORT-mediated decrease in hippocampal and hypothalamic glucocorticoid receptor mRNA levels is not the only mechanism contributing to the maintenance of a robust HPA response after repeated stress. Similarly, we postulate that the relative shift from CRH to AVP in the PVN after repeated stress is mediated by both a greater sensitivity of AVP to CORT negative feedback and CORT-independent mechanisms.

Stress and anxiety are mainly regulated by amygdala and hypothalamic circuitries involving several neurotransmitter systems and providing physiological responses to peripheral organs via the hypothalamic-pituitary-adrenal axis and other pathways. The role of endogenous opioid peptides in this process is largely unknown. Here we show for the first time that anxiolytic parameters of explorative behavior in mice lacking prodynorphin were increased 2-4-fold in the open field, the elevated plus maze and the light-dark test. Consistent with this, treatment of wild-type mice with selective kappa-opioid receptor antagonists GNTI or norbinaltorphimine showed the same effects. Furthermore, treatment of prodynorphin knockout animals with U-50488H, a selective kappa-opioid receptor agonist, fully reversed their anxiolytic phenotype. These behavioral data are supported by an approximal 30% reduction in corticotropin-releasing hormone (CRH) mRNA expression in the hypothalamic paraventricular nucleus and central amygdala and an accompanying 30-40% decrease in corticosterone serum levels in prodynorphin knockout mice. Although stress-induced increases in corticosterone levels were attenuated in prodynorphin knockout mice, they were associated with minor increases in depression-like behavior in the tail suspension and forced swim tests. Taken together, our data suggest a pronounced impact of endogenous prodynorphin-derived peptides on anxiety, but not stress coping ability and that these effects are mediated via kappa-opioid receptors. The delay in the behavioral response to kappa-opioid receptor agonists and antagonist treatment suggests an indirect control level for the action of dynorphin, probably by modulating the expression of CRH or neuropeptide Y, and subsequently influencing behavior.

Postnatal rearing conditions influence the development of hypothalamic-pituitary-adrenal (HPA) responses to stress in the rat. Thus, postnatal handling dampens HPA responsivity to stress, while prolonged periods of maternal separation have the opposite effect. HPA responses to stress are initiated by the release of corticotropin-releasing factor and/or arginine vasopressin from the neurones of the paraventricular nucleus of the hypothalamus (PVNh). A major source of input to the PVNh arises from brainstem noradrenergic neurones with signalling occurring via alpha1 adrenoreceptors. We examined the noradrenergic response to stress in the PVNh in adult animals exposed to daily periods of handling or maternal separation over the first 2 weeks of life using microdialysis in conscious animals. Maternal separation increased, while handling greatly decreased and norepinepherine responses to restraint stress in the PVNh as compared to non-handled controls; the same pattern was observed for plasma adrenocorticotropic hormone (ACTH) responses to stress. Rearing condition did not affect either alpha1 or alpha2 receptor levels in the PVNh. However, alpha2 receptor binding levels in the noradrenergic cell body regions of the locus coeruleus and the n. tractus solitarius were significantly increased in handled animals. These alpha2 receptors are principally located on noradrenergic neurones (i.e. autoreceptors) and inhibit noradrenaline release at terminal sites. The effects on alpha2 receptor levels could serve as a mechanism for the differences in stress-induced noradrenaline levels in the PVNh and in HPA activity among handled vs non-handled and maternal separation animals. Thus, early life events may serve to influence the differentiation of noradrenergic neurones and thus alter HPA responses stress in adulthood.

Corticotropin-releasing factor was administered into the lateral cerebral ventricles of rats. Sixty minutes later, animals were tested in an open field conflict test or in their home cages for a variety of behaviors which have been shown to be related to the degree of responsiveness to novelty. CRF, in a dose related fashion, altered the frequency of those behaviors which are normally expressed in response to the novel environment. Specifically, CRF caused an increase in grooming and decreases in the amount of rearing, the number of approaches to a food pellet placed in the center of the open field, the amount of food eaten in both the open field and the home cage and a decrease in the mean amount of food eaten per approach to the food pedestal.

The bed nucleus of the stria terminalis (BNST) plays an important role in the regulation of the hypothalamic-pituitary-adrenal (HPA) axis during stress and it is a major extrahypothalamic relay to the paraventricular nucleus of the hypothalamus (PVN) from the amygdala and the hippocampus. In this review, we discuss the anatomical, neurochemical and behavioral evidence that substantiate a role for noradrenergic terminals of the anterior BNST in the regulation of the HPA axis. We propose the hypothesis that BNST noradrenaline (NA) participates in the regulation of the hippocampal inhibitory influence on the HPA axis activation. The observation that NA exerts a tonic inhibitory effect upon glutamatergic transmission in the anterior BNST supports this hypothesis. We also discuss the known mechanisms involved in the regulation of BNST NA extracellular levels and the possible interactions between NA and corticotropin-releasing hormone (CRH), and of CRH with glutamate (GLU) in the regulation of the HPA axis activity exerted by the BNST. The evidence discussed in the present review situates the BNST as a key extrahypothalamic center that relays and integrates limbic and autonomic information related to stress responses suggesting that dysregulation in the functioning of the BNST may underlie the pathophysiology of stress-related psychiatric disorders.

The hypothalamic-pituitary-adrenal (HPA) axis maintains basal and stress-related homeostasis in vertebrates. Skin expresses all elements of the HPA axis including corticotropin-releasing hormone (CRH), proopiomelanocortin (POMC), ACTH, β-endorphin (β-END) with corresponding receptors, the glucocorticoidogenic pathway, and the glucocorticoid receptor (GR). To test the hypothesis that cutaneous responses to environmental stressors follow the organizational structure of the central response to stress, the activity of the "cutaneous HPA" axis homolog was investigated after exposure to ultraviolet radiation (UVR) wavelengths of UVA (320-400 nm), UVB (280-320 nm), and UVC (100-280 nm) in human skin organ culture and in co-cultured keratinocytes/melanocytes. The level of stimulation of CRH, POMC, MC1R, MC2R, CYP11A1, and CYP11B1 genes was dependent on UV wavelengths and doses, with the highest effects observed for highly energetic UVC and UVB. ELISA and Western assays showed significant production of CRH, POMC, ACTH, and CYP11A1 proteins and of cortisol, with a decrease in GR expression only after UVB and UVC. However, β-END expression was also stimulated by UVA. Immunocytochemistry localized the deposition of the aforesaid antigens predominantly to the epidermis with additional accumulation of CRH, β-END, and ACTH in the dermis. UVR-stimulated CYP11A1 expression was seen in the basal layer of the epidermis and cells of adjacent dermis. Thus, the capacity to activate or change the spatial distribution of the cutaneous HPA axis elements is dependent on highly energetic wavelengths (UVC and UVB), implying a dependence of a local stress response on their noxious activity with overlapping or alternative mechanisms activated by UVA.

In the present experiments, we characterized the action of human/rat corticotropin-releasing factor (h/rCRF) and acute stress (1 hr of immobilization) on hippocampus-dependent learning and on synaptic plasticity in the mouse hippocampus. We first showed that h/rCRF application and acute stress facilitated (primed) long-term potentiation of population spikes (PS-LTP) in the mouse hippocampus and enhanced context-dependent fear conditioning. Both the priming of PS-LTP and the improvement of context-dependent fear conditioning were prevented by the CRF receptor antagonist [Glu(11,16)]astressin. PS-LTP priming and improved learning were also reduced by the protein kinase C inhibitor bisindolylmaleimide I. Acute stress induced the activation of Ca2+/calmodulin-dependent kinase II (CaMKII) 2 hr after the end of the stress session. The CaMKII inhibitor KN-62 antagonized the stress-mediated learning enhancement, however, with no effect on PS-LTP persistence. Thus, long-lasting increased neuronal excitability as reflected in PS-LTP priming appeared to be essential for the enhancement of learning in view of the observation that inhibition of PS-LTP priming was associated with impaired learning. Conversely, it was demonstrated that inhibition of CaMKII activity reduced contextual fear conditioning without affecting PS-LTP priming. This observation suggests that priming of PS-LTP and activation of CaMKII represent two essential mechanisms that may contribute independently to long-term memory.

BACKGROUND

Repetitive transcranial magnetic stimulation is increasingly used as a therapeutic tool in psychiatry and has been demonstrated to attenuate the activity of the stress hormone system. Stress-induced structural remodeling in the adult hippocampus may provide a cellular basis for understanding the impairment of neural plasticity in depressive illness. Accordingly, reversal of structural remodeling might be a desirable goal for antidepressant therapy. The present study investigated the effect of chronic psychosocial stress and concomitant repetitive transcranial magnetic stimulation treatment on stress hormone regulation and hippocampal neurogenesis.

METHODS

Adult male rats were submitted to daily psychosocial stress and repetitive transcranial magnetic stimulation (20 Hz) for 18 days. Cell proliferation in the dentate gyrus was quantified by using BrdU immunohistochemistry, and both the proliferation rate of progenitors and the survival rate of BrdU-labeled cells were evaluated. To characterize the activity of the hypothalamic-pituitary-adrenocortical system, plasma corticotropin and corticosterone concentrations were measured.

RESULTS

Chronic psychosocial stress resulted in a significant increase of stress hormone levels and potently suppressed the proliferation rate and survival of the newly generated hippocampal granule cells. Concomitant repetitive transcranial magnetic stimulation treatment normalized the stress-induced elevation of stress hormones; however, despite the normalized activity of the hypothalamic-pituitary-adrenocortical system, the decrement of hippocampal cell proliferation was only mildly attenuated by repetitive transcranial magnetic stimulation, while the survival rate of BrdU-labeled cells was further suppressed by the treatment.

CONCLUSIONS

These results support the notion that attenuation of the hypothalamic-pituitary-adrenocortical system is an important mechanism underlying the clinically observed antidepressant effect of repetitive transcranial magnetic stimulation, whereas this experimental design did not reveal beneficial effects of repetitive transcranial magnetic stimulation on adult hippocampal neurogenesis.

Binge drinking is prevalent and has serious biomedical consequences. In children, adolescents, and young adults, it is a prominent risk factor for later development of alcohol-use disorders. Many preclinical models have been employed to study the genetic risks for and biomedical consequences of alcohol drinking. However, these models historically did not result in blood-alcohol concentrations (BACs) exceeding 80 mg%; this relatively modest level is the threshold that currently defines a binge session, according to the NIAAA and CDC. Nevertheless, in alcohol-dependent rodents, binge drinking has been well documented. Key neurobiological substrates localized to brain reward and stress systems have been identified. Studies of newer models of binge drinking without dependence are reviewed here. In these models, rodents, non-human primates, and flies will drink enough to reach high BACs. They often display observable signs of intoxication. The neurobiological consequences of these episodes of binge drinking without dependence are reviewed, and preliminary evidence for roles for GABA, glutamate, opioid peptides, and corticotropin releasing factor are discussed, as is the need for more work to identify the antecedents and consequences of binge drinking in both animal models and humans.

Robust physiological actions of the neuropeptide corticotropin-releasing hormone (CRH) on hippocampal pyramidal neurons have been demonstrated, which may contribute to synaptic efficacy and to learning and memory processes. These excitatory actions of the peptide, as well as the expression of the CRH receptor type that mediates them, are particularly prominent during early postnatal life, suggesting that endogenous CRH may contribute to processes involved in maturation of hippocampal circuitry. To further elucidate the function(s) of endogenous CRH in developing hippocampus, we used neurochemical and quantitative stereological methods to characterize in detail CRH-expressing neuronal populations during postnatal hippocampal differentiation. These experiments revealed progressively increasing numbers of CRH-expressing neurons in developing hippocampus that peaked on postnatal day 11-18 and then declined drastically to adult levels. These cells belonged to several discrete populations, distinguished by GAD67 mRNA expression, morphology, and distinct spatiotemporal distribution profiles. Importantly, a novel population of Cajal-Retzius-like CRH-expressing neurons was characterized that exists only transiently in early postnatal hippocampus and is positioned to contribute to the establishment of hippocampal connectivity. These findings suggest novel, age-specific roles for CRH in regulating early developmental events in the hippocampal formation.