OBJECTIVE

Footshock stress reliably reinstates heroin seeking in rats, but the time course of the development of this effect following drug withdrawal is not known. Here we studied the effect of intermittent footshock stress on reinstatement of heroin seeking following different withdrawal periods (1-66 days). We also studied whether changes in corticotropin-releasing factor (CRF) mRNA in the central nucleus of the amygdala (CeA) and the bed nucleus of the stria terminalis (BNST) are correlated with this reinstatement after 1 day and 6 days of heroin withdrawal.

METHODS

Rats were trained to self-administer heroin (9 h/day; 0.1 mg/kg per infusion) for 10 days. Tests for extinction behavior and footshock-induced reinstatement of heroin seeking were then conducted after 1, 6, 12, 25, or 66 days of heroin withdrawal. On the test day, rats were given five to ten 60-min extinction sessions until they reached the extinction criterion of less than 15 responses per 60 min on the lever previously associated with heroin. Rats were then exposed to intermittent foot-shock (0.8 mA; 10 min), and lever-pressing behavior was recorded for 120 min.

RESULTS

Reinstatement of lever-pressing behavior by footshock followed an inverted U-shaped curve with maximal responding after 6 days and 12 days of heroin withdrawal. Surprisingly, foot-shock did not reinstate lever-pressing behavior on day 1 of withdrawal. Lever pressing during extinction, prior to exposure to footshock, also followed an inverted U-shaped curve, with higher responding after 6, 12, and 25 days of heroin withdrawal. Finally, compared with control groups not exposed to shock, CRF mRNA levels in response to footshock were increased in the CeA (day 1 of withdrawal) and the dorsal BNST (day 1 and day 6), but not in the ventral BNST.

CONCLUSIONS

The duration of the heroin withdrawal period is an important factor in the manifestation of (1) footshock stress-induced reinstatement of heroin seeking and (2) extinction of the heroin-reinforced behavior. Finally, the time-dependent changes in footshock stress-induced reinstatement following withdrawal from heroin were not correlated with alterations in CRF mRNA in the CeA and BNST.

Research findings on the hypothalamic-pituitary-adrenal (HPA) axis and pediatric depression reflect a variety of methodological approaches that tap different facets of HPA-axis functions. Partly owing to the methodological heterogeneity of studies, descriptive reviews of this area have produced inconsistent conclusions. Therefore, we conducted formal meta-analyses of pertinent studies in order to advance our understanding of HPA-axis dysregulation in pediatric depression. We examined: (a) 17 published studies of HPA-axis response to the dexamethasone suppression test (DST) in depressed youth (DST; N=926) and (b) 17 studies of basal HPA-axis functioning (N=1332). We also examined descriptively studies that used corticotropin-releasing hormone (CRH) infusion, and those that used psychological probes of the HPA-axis. The global standardized mean effect size difference in HPA-axis response to the DST between depressed and non-depressed youth was 0.57, z=4.18, p<0.01. The global standardized mean difference effect size in basal HPA-axis functioning was 0.20, z=4.53, p<0.01. Age, sex, timing of sampling, dexamethasone dosage, or type of control group was not a significant source of variability for the DST or basal studies. In addition, when compared to non-depressed peers, depressed youth have a normative response to CRH infusion but an overactive response to psychological stressors. In conclusion, the HPA-axis system tends to be dysregulated in depressed youth, as evidenced by atypical responses to the DST, higher baseline cortisol values, and an overactive response to psychological stressors. This pattern of dysregulation suggests anomalies within the axis's negative feedback system and CRH production, but intact pituitary and adrenal sensitivity.

The discovery of corticotropin-releasing factor (CRF) or CRH defining the upper regulatory arm of the hypothalamic-pituitary-adrenal (HPA) axis, along with the identification of the corresponding receptors (CRFRs 1 and 2), represents a milestone in our understanding of central mechanisms regulating body and local homeostasis. We focused on the CRF-led signaling systems in the skin and offer a model for regulation of peripheral homeostasis based on the interaction of CRF and the structurally related urocortins with corresponding receptors and the resulting direct or indirect phenotypic effects that include regulation of epidermal barrier function, skin immune, pigmentary, adnexal, and dermal functions necessary to maintain local and systemic homeostasis. The regulatory modes of action include the classical CRF-led cutaneous equivalent of the central HPA axis, the expression and function of CRF and related peptides, and the stimulation of pro-opiomelanocortin peptides or cytokines. The key regulatory role is assigned to the CRFR-1α receptor, with other isoforms having modulatory effects. CRF can be released from sensory nerves and immune cells in response to emotional and environmental stressors. The expression sequence of peptides includes urocortin/CRF→pro-opiomelanocortin→ACTH, MSH, and β-endorphin. Expression of these peptides and of CRFR-1α is environmentally regulated, and their dysfunction can lead to skin and systemic diseases. Environmentally stressed skin can activate both the central and local HPA axis through either sensory nerves or humoral factors to turn on homeostatic responses counteracting cutaneous and systemic environmental damage. CRF and CRFR-1 may constitute novel targets through the use of specific agonists or antagonists, especially for therapy of skin diseases that worsen with stress, such as atopic dermatitis and psoriasis.

Among the more consistent observations in patients with major depression is dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis presenting as elevation of basal cortisol, dexamethasone-mediated negative feedback resistance, increased cerebrospinal fluid levels of corticotropin-releasing factor (CRF), and a blunted adrenocorticotropic hormone (ACTH) response to challenge with exogenous CRF. These features appear to be state, rather than trait markers, and are normalized upon successful treatment. These pathophysiologic adaptations may arise from defects in central drive to the neuroendocrine hypothalamus, disruption of normal adrenocortical hormone receptor function or a modification of HPA axis function at any level. Functional assessment of the HPA axis is thought to provide a window into central nervous system operation that may be of diagnostic value in this and other affective disorders regardless of whether CRF and glucocorticoids are directly involved in the origin of major depression or merely exacerbate the consequences of other primary defects.

Evidence from many different laboratories using a variety of experimental techniques and animal species indicates that the amygdala plays a crucial role in conditioned fear and anxiety, as well as attention. Many amygdaloid projection areas are critically involved in specific signs used to measure fear and anxiety. Electrical stimulation of the amygdala elicits a pattern of behaviors that mimic natural or conditioned fear. Lesions of the amygdala block innate or conditioned fear, as well as various measures of attention, and local infusions of drugs into the amygdala have anxiolytic effects in several behavioral tests. N-methyl-D-aspartate (NMDA) receptors in the amygdala may be important in the acquisition of conditioned fear, whereas non-NMDA receptors are important for the expression of conditioned fear. The peptide corticotropin-releasing hormone appears to be especially important in fear or anxiety and may act within the amygdala to orchestrate parts of the fear reaction.

Activation of the inflammatory immune system provokes numerous neuroendocrine and neurotransmitter changes, many of which are similar to those provoked by physical or psychological stressors. These findings, among others, have led to the suggestion that the brain translates immune activation much as if it were a stressor. In this review, I provide synopses of the effects of traditional stressors on the release of corticotropin-releasing hormones at hypothalamic and extrahypothalamic sites, variations of serotonin and its receptors and changes of brain-derived neurotrophic factor (BDNF). These effects are similar to those elicited by activation of the inflammatory immune system, particularly the impact of the immune-signalling molecules interleukin-1 beta, interleukin-6, tumour necrosis factor-alpha and interferon-alpha on neuroendocrine, neurotransmitter and BDNF function. In addition, it is reported that stressors and cytokines may synergistically influence biological and behavioural processes and that these treatments may have long-term ramifications through the sensitization of processes associated with stress responses. Finally, I present an overview of the depressogenic actions of these cytokines in rodent models and in humans, and I provide provisional suggestions (and caveats) about the mechanisms by which cytokines and stressors might culminate in major depressive disorder.

Child abuse is associated with markedly elevated rates of major depression and other psychiatric disorders in adulthood. This article reviews preclinical studies examining the effects of early stress, factors that modify the impact of these experiences, and neurobiological changes associated with major depression. Preclinical studies demonstrate that early stress can alter the development of the hypothalamic-pituitary-adrenal axis, hypothalamic and extrahypothalamic corticotropin releasing hormone, monoaminergic, and gamma-aminobutyric acid/benzodiazepine systems. Stress has also been shown to promote structural and functional alterations in brain regions similar to those seen in adults with depression. Emerging data suggest, however, that the long-term effects of early stress can be moderated by genetic factors and the quality of the subsequent caregiving environment. These effects also can be prevented or reversed with various pharmacologic interventions. Preclinical studies of early stress can provide valuable insights in understanding the pathophysiology and treatment of major depression. They also can provide an important tool to use to investigate interactions between genes and environments in determining an individual's sensitivity to stress. More research is needed to understand how inherent factors interact with experiences of abuse and other psychosocial factors to confer vulnerability to develop depression.

Expression of c-Fos, or other immediate early gene products, by individual neurons can be used as a marker of cell activation, making staining of these proteins an extremely useful technique for functional anatomical mapping of neuroendocrine systems. Because these proteins are located in the nucleus, identification of the phenotype of the activated neuron using substances located within the cytoplasm can be accomplished with standard double-labeling immunocytochemical techniques. Although it is clear that neurons have the capacity to express a number of immediate early gene products, what remains to be established is whether there is a different pattern of expression following various stimuli. In our studies, we focus primarily on expression of one immediate early gene product, the c-Fos protein. We also include some experiments using expression of other members of the Fos family and Jun proteins as markers for neuronal activation. Our studies describe uses of c-Fos expression in both parvocellular and magnocellular hypothalamic systems to address the following issues: (a) identification of neuroendocrine cells activated by specific treatments and conditions, (b) ascertainment of functional differences in subpopulations activated by specific stimuli, (c) evaluation of neuronal activity in complex areas containing multiple neuroendocrine systems, (d) identification of other brain areas activated in conjunction with neuroendocrine systems following specific stimuli, (e) analysis of connectivity of activated neuroendocrine systems with other parts of the brain, and (f) identification of stimuli that decrease neuronal activity. The neuroendocrine systems studied include those that secrete arginine vasopressin (AVP), oxytocin (OT), corticotropin-releasing hormone (CRH), luteinizing hormone-releasing hormone (LHRH), and dopamine (DA). The use of c-Fos expression has permitted functional neuroanatomical mapping of these systems in response to specific stimuli such as cholecystokinin (CCK), hyperosmolality, and volume depletion, or during various physiological states such as the proestrous ovulatory luteinizing hormone (LH) surge and lactation. Although the use of c-Fos as a marker of neuronal activation will continue to be an extremely powerful technique, future studies will also be directed at relating immediate early gene expression to changes in neuroendocrine gene expression. To this end, we have shown that both c-Fos and c-Jun are expressed in neuroendocrine neurons in response to a number of stimuli, setting the stage for potential regulatory drive to genes containing AP-1 binding sites.

Abnormal signaling at corticotropin-releasing factor CRF1 and CRF2 receptors might contribute to the pathophysiology of stress-related disorders such as anxiety, depression and eating disorders, in addition to cardiac and inflammatory disorders. Recently, molecular characterization of CRF1 and CRF2 receptors and the cloning of novel ligands--urocortin, stresscopin-related peptide/urocortin II, and stresscopin/urocortin III--have revealed a far-reaching physiological importance for the family of CRF peptides. Although the physiological roles of the CRF2 receptor remain to be defined, the preclinical and clinical development of specific small-molecule antagonists of the CRF1 receptor opens new avenues for the treatment of psychiatric and neurological disorders.

Chronic stress impairs learning and memory in humans and rodents and disrupts long-term potentiation (LTP) in animal models. These effects are associated with structural changes in hippocampal neurons, including reduced dendritic arborization. Unlike the generally reversible effects of chronic stress on adult rat hippocampus, we have previously found that the effects of early-life stress endure and worsen during adulthood, yet the mechanisms for these clinically important sequelae are poorly understood. Stress promotes secretion of the neuropeptide corticotropin-releasing hormone (CRH) from hippocampal interneurons, activating receptors (CRF(1)) located on pyramidal cell dendrites. Additionally, chronic CRF(1) occupancy negatively affects dendritic arborization in mouse organotypic slice cultures, similar to the pattern observed in middle-aged, early-stressed (CES) rats. Here we found that CRH expression is augmented in hippocampus of middle-aged CES rats, and then tested whether the morphological defects and poor memory performance in these animals involve excessive activation of CRF(1) receptors. Central or peripheral administration of a CRF(1) blocker following the stress period improved memory performance of CES rats in novel-object recognition tests and in the Morris water maze. Consonant with these effects, the antagonist also prevented dendritic atrophy and LTP attenuation in CA1 Schaffer collateral synapses. Together, these data suggest that persistently elevated hippocampal CRH-CRF(1) interaction contributes importantly to the structural and cognitive impairments associated with early-life stress. Reducing CRF(1) occupancy post hoc normalized hippocampal function during middle age, thus offering potential mechanism-based therapeutic interventions for children affected by chronic stress.

The recent cloning of a second estrogen receptor (ER) provided a new tool to investigate and clarify how estrogens are capable of communicating with the brain and influence gene expression and neural function. The purpose of the present study was to define the neuroanatomical organization of each receptor subtype using a side-by-side approach and to characterize the cellular population (s) expressing the ERbeta transcript in the endocrine hypothalamus using immunohistochemistry combined with in situ hybridization. Axonal transport inhibition was accomplished to cause neuropeptide accumulation into the cytoplasm and thus facilitate the detection of all positive luteinizing hormone-releasing hormone (LHRH), corticotropin-releasing factor (CRF), vasopressin (AVP), oxytocin (OT), gastrin-related peptide (GRP), and enkephalin (ENK) neurons. The genes encoding either ERalpha or -beta were expressed in numerous limbic-associated structures, and fine differences were found in terms of intensity and positive signal. Such phenomenon is best represented by the bed nucleus of the stria terminalis (BnST) and preoptic area/anterior hypothalamus, where the expression pattern of both transcripts differed across subnuclei. The novel ER was also found to be expressed quite exclusively in other hypothalamic nuclei, including the supraoptic (SON) and selective compartments (magnocellular and autonomic divisions) of the paraventricular nucleus (PVN). A high percentage of the ERbeta-expressing neurons located in the ventro- and dorsomedial PVN are of OT type; 40% of the OT-ir cells forming the medial magnocellular and ventromedial parvocellular PVN showed a clear hybridization signal for ERbeta mRNA, whereas a lower percentage (15-20%) of OT neurons were positive in the caudal parvocellular PVN and no double-labeled cells were found in the rostral PVN and other regions of the brain with the exception of the SON. Very few AVP-ir neurons expressing ERbeta transcript were found throughout the rat brain, although the medial PVN displayed some scattered double-labeled cells (<5%). Quite interestingly, the large majority of the ERbeta-positive cells in the caudal PVN were colocalized within CRF-ir perikarya. Indeed, more than 60-80% of the CRF-containing cells located in the caudolateral division of the parvocellular PVN exhibited a positive hybridization signal for ERbeta mRNA, whereas very few (<5%) neuroendocrine CRF-ir parvocellular neurons of the medial PVN expressed the gene encoding ERbeta. A small percentage of ERbeta-expressing cells in the dorsocaudal and ventromedial zones of the parvocellular PVN were also ENK positive. The ventral zone of the medial parvocellular PVN also displayed GRP-ir neurons, but no convincing hybridization signal for ERbeta was detected in this neuronal population. Finally, as previously described for the gene encoding the classic ER, LHRH neurons of both intact and colchicine-pretreated animals did not express the novel estrogen receptor. This study shows a differential pattern of expression of both receptors in the brain of intact rats and that ERbeta is expressed at various levels in distinct neuropeptidergic populations, including OT, CRF, and ENK. The influence of estrogen in mediating genomic and neuronal responses may therefore take place within these specific cellular groups in the brains of cycling as well as intact male mammals.

The hypothalamo-pituitary-adrenal (HPA) axis is involved in all aspects of cocaine self-administration. Corticosterone seems to be crucial for the acquisition of drug use since self-administration does not occur unless this stress hormone is increased above a critical reward threshold. Increasing circulating levels of corticosterone also augments sensitivity to low doses of cocaine, possibly from a sensitization-associated phenomenon involving dopamine, suggesting that exposure to stress can increase individual vulnerability to cocaine. Drugs affecting the synthesis and/or secretion of corticosterone decrease ongoing, low-dose cocaine self-administration. When higher doses falling on the descending limb of the cocaine dose-response curve are self-administered, plasma corticosterone can still reach this reward threshold even when synthesis is inhibited and drug intake is not affected. Corticotropin-releasing hormone (CRH) seems to play a more prominent role in the maintenance of cocaine self-administration and may even be involved in the incentive motivation for the drug. Corticosterone and CRH are also critical for the stress- and cue-induced reinstatement of extinguished cocaine-seeking behavior. Therefore, cocaine self-administration may represent an attempt to seek out specific sensations, with the internal state produced being very similar to that perceived by individuals who engage in risky, thrill-seeking behavior. During abstinence, exposure to stressors or cocaine-associated cues can stimulate the HPA axis to remind the individual about the effects of cocaine, thus producing craving and promoting relapse. Stress reduction, either alone or in combination with pharmacotherapies targeting the HPA axis may prove beneficial in reducing cravings and promoting abstinence in individuals seeking treatment for cocaine addiction.

Corticotropin-releasing factor (CRF) is a major hypophysiotropic peptide regulating pituitary-adrenal response to stress, and it is also widely expressed in the central nervous system. The recent cloning of cDNAs encoding the human and rat CRF receptors has enabled us to map the distribution of cells expressing CRF receptor mRNA in rat brain and pituitary by in situ hybridization. Receptor expression in the forebrain is dominated by widespread signal throughout all areas of the neo-, olfactory, and hippocampal cortices. Other prominent sites of CRF receptor mRNA expression include subcortical limbic structures in the septal region and amygdala. In the diencephalon, low levels of expression are seen in a few discrete ventral thalamic and medial hypothalamic nuclei. CRF receptor expression in hypothalamic neurosecretory structures, including the paraventricular nucleus and median eminence, is generally low. In the brainstem, certain relay nuclei associated with the somatic (including trigeminal), auditory, vestibular, and visceral sensory systems, constituted prominent sites of CRF receptor mRNA expression. In addition, high levels of this transcript are present in the cerebellar cortex and deep nuclei, along with many precerebellar nuclei. In the pituitary, moderate levels of CRF receptor mRNA expression were detected throughout the intermediate lobe and in a subset of cells in the anterior lobe identified as corticotropes by concurrent immunolabeling. Overall, the central distribution of CRF receptor mRNA expression is similar to, though more expansive than, that of regions reported to bind CRF, and it shows limited overlap with loci expressing CRF-binding protein. Interestingly, CRF receptor mRNA is low or undetectable in several cell groups implicated as central sites of CRF action.

Corticotropin-releasing hormone (Crh), a 41-residue polypeptide, activates two G-protein-coupled receptors, Crhr1 and Crhr2, causing (among other transductional events) phosphorylation of the transcription factor Creb. The physiologic role of these receptors is only partially understood. Here we report that male, but not female, Crhr2-deficient mice exhibit enhanced anxious behaviour in several tests of anxiety in contrast to mice lacking Crhr1. The enhanced anxiety of Crhr2-deficient mice is not due to changes in hypothalamic-pituitary-adrenal (HPA) axis activity, but rather reflects impaired responses in specific brain regions involved in emotional and autonomic function, as monitored by a reduction of Creb phosphorylation in male, but not female, Crhr2-/- mice. We propose that Crhr2 predominantly mediates a central anxiolytic response, opposing the general anxiogenic effect of Crh mediated by Crhr1. Neither male nor female Crhr2-deficient mice show alterations of baseline feeding behaviour. Both respond with increased edema formation in response to thermal exposure, however, indicating that in contrast to its central role in anxiety, the peripheral role of Crhr2 in vascular permeability is independent of gender.

Drug addiction is a chronically relapsing disorder characterized by a compulsion to seek and take drugs, the development of dependence, and the manifestation of a negative emotional state when the drug is removed. Activation of brain stress systems is hypothesized to be a key element of the negative emotional state produced by dependence that drives drug-seeking through negative reinforcement mechanisms, defined as the "dark side" of addiction. The focus of the present review is on the role of corticotropin-releasing factor (CRF) and CRF-related peptides in the dark side of addiction. CRF is a key mediator of the hormonal, autonomic, and behavior responses to stressors. Emphasis is placed on the role of CRF in extrahypothalamic systems in the extended amygdala, including the central nucleus of the amygdala, bed nucleus of the stria terminalis, and a transition area in the shell of the nucleus accumbens, in the dark side of addiction. The urocortin/CRF(2) systems have been less explored, but results suggest their role in the neuroadaptation associated with chronic drug use, sometimes in opposition to the effects produced by the CRF(1) receptor. Compelling evidence argues that the CRF stress system, including its activation of the hypothalamic-pituitary-adrenal axis, plays a key role in engaging the transition to dependence and maintaining dependence once it is initiated. Understanding the role of the CRF systems in addiction not only provides insight into the neurobiology of the dark side of addiction, but also provides novel targets for identifying vulnerability to addiction and the treatment of addiction.

Receptors for corticotropin-releasing factor (CRF) are members of a family of G protein-coupled receptors ("Family B") that respond to a variety of structurally dissimilar releasing factors, neuropeptides, and hormones (including secretin, growth hormone-releasing factor, calcitonin, parathyroid hormone, pituitary adenylate cyclase-activating polypeptide, and vasoactive intestinal polypeptide) and signal through the cyclic AMP and/or calcium pathways. To date, three genes encoding additional CRF-like peptides (urocortins) have been identified in mammals. The urocortins and CRF bind with differential ligand selectivity at the two mammalian CRF receptors. This report was prepared by the International Union of Pharmacology Subcommittee on CRF Receptors, to summarize the current state of CRF receptor biology and to propose changes in the classification and nomenclature of CRF ligands and receptors.

BACKGROUND

There are few large series of patients with ectopic, nonpituitary, corticotropin (ACTH) secretion (EAS).

OBJECTIVE

The objective of this study was to analyze the clinical, biochemical, and radiological features, management, and treatment outcome of patients with EAS.

METHODS

This was a retrospective case-record study.

METHODS

The setting for this study was a tertiary referral hospital center.

METHODS

Forty patients with EAS were studied.

METHODS

Clinical, biochemical, and radiological features and response to therapy and survival were measured.

RESULTS

The median follow-up was 5 yr (range, 2-30 yr). None of the dynamic tests achieved 100% accuracy, but bilateral inferior petrosal sinus sampling showed an absent central gradient in all but one case (one of 12). Imaging correctly identified the lesion at first investigation in 65% of cases. Bronchial carcinoid tumors were the most common cause of EAS (n = 12; 30%), followed by other neuroendocrine tumors (n = 13, 32.5%). In 12.5% of patients, the source of EAS was never found. Octreotide scintigraphy and whole-body venous sampling were of limited value. Surgical attempt at curative resection was successful in 83% (10 of 12) of patients with bronchial carcinoid tumors; others responded generally well to adrenolytic therapy or bilateral adrenalectomy. Tumor histology and the presence of distant metastases were the main predictors of overall survival (P < 0.05).

CONCLUSIONS

A variety of tests and imaging studies are necessary for the correct diagnosis of the EAS, but even then, up to 20% of cases present a covert or occult EAS syndrome. These cases require a prolonged follow-up, review, and repetition of diagnostic tests and scans.

OBJECTIVE

Intestinal barrier impairment is incriminated in the pathophysiology of intestinal gut disorders associated with psychiatric comorbidity. Increased intestinal permeability associated with upload of lipopolysaccharides (LPS) translocation induces depressive symptoms. Gut microbiota and probiotics alter behavior and brain neurochemistry. Since Lactobacillus farciminis suppresses stress-induced hyperpermeability, we examined whether (i) L. farciminis affects the HPA axis stress response, (ii) stress induces changes in LPS translocation and central cytokine expression which may be reversed by L. farciminis, (iii) the prevention of "leaky" gut and LPS upload are involved in these effects.

METHODS

At the end of the following treatments female rats were submitted to a partial restraint stress (PRS) or sham-PRS: (i) oral administration of L. farciminis during 2 weeks, (ii) intraperitoneal administration of ML-7 (a specific myosin light chain kinase inhibitor), (iii) antibiotic administration in drinking water during 12 days. After PRS or sham-PRS session, we evaluated LPS levels in portal blood, plasma corticosterone and adrenocorticotropic hormone (ACTH) levels, hypothalamic corticotropin releasing factor (CRF) and pro-inflammatory cytokine mRNA expression, and colonic paracellular permeability (CPP).

RESULTS

PRS increased plasma ACTH and corticosterone; hypothalamic CRF and pro-inflammatory cytokine expression; CPP and portal blood concentration of LPS. L. farciminis and ML-7 suppressed stress-induced hyperpermeability, endotoxemia and prevented HPA axis stress response and neuroinflammation. Antibiotic reduction of luminal LPS concentration prevented HPA axis stress response and increased hypothalamic expression of pro-inflammatory cytokines.

CONCLUSIONS

The attenuation of the HPA axis response to stress by L. farciminis depends upon the prevention of intestinal barrier impairment and decrease of circulating LPS levels.

Over the past few decades, corticotropin-releasing factor (CRF) signaling pathways have been shown to be the main coordinators of the endocrine, behavioral, and immune responses to stress. Emerging evidence also links the activation of CRF receptors type 1 and type 2 with stress-related alterations of gut motor function. Here, we review the role of CRF receptors in both the brain and the gut as part of key mechanisms through which various stressors impact propulsive activity of the gastrointestinal system. We also examine how these mechanisms translate into the development of new approaches for irritable bowel syndrome, a multifactorial disorder for which stress has been implicated in the pathophysiology.

A conceptual structure for drug addiction focused on allostatic changes in reward function that lead to excessive drug intake provides a heuristic framework with which to identify the neurobiologic neuroadaptive mechanisms involved in the development of drug addiction. The brain reward system implicated in the development of addiction is comprised of key elements of a basal forebrain macrostructure termed the extended amygdala and its connections. Neuropharmacologic studies in animal models of addiction have provided evidence for the dysregulation of specific neurochemical mechanisms not only in specific brain reward circuits (opioid peptides, gamma-aminobutyric acid, glutamate and dopamine) but also recruitment of brain stress systems (corticotropin-releasing factor) that provide the negative motivational state that drives addiction, and also are localized in the extended amygdala. The changes in the reward and stress systems are hypothesized to maintain hedonic stability in an allostatic state, as opposed to a homeostatic state, and as such convey the vulnerability for development of dependence and relapse in addiction.

Organisms exposed to challenging stimuli that alter the status quo inside or outside of the body are required for survival purposes to generate appropriate coping responses that counteract departures from homeostasis. Identification of an executive control mechanism within the brain capable of coordinating the multitude of endocrine, physiological, and functional coping responses has high utility for understanding the response of the organism to stressor exposure under normal or pathological conditions. The corticotropin-releasing factor (CRF)/urocortin family of neuropeptides and receptors constitutes an affective regulatory system due to the integral role it plays in controlling neural substrates of arousal, emotionality, and aversive processes. In particular, available evidence from pharmacological intervention in multiple species and phenotyping of mutant mice shows that CRF/urocortin systems mediate motor and psychic activation, stimulus avoidance, and threat recognition responses to aversive stimulus exposure. It is suggested that affective regulation is exerted by CRF/urocortin systems within the brain based upon the sensitivity of local brain sites to CRF/urocortin ligand administration and the appearance of hypothalamo-pituitary-adrenocortical activation following stressor exposure. Moreover, these same stress neuropeptides may constitute a mechanism for learning to avoid noxious stimuli by facilitating the formation of so-called emotional memories. A conceptual framework is provided for extrapolation of animal model findings to humans and for viewing CRF/urocortin activation as a continuum measure linking normal and pathological states.

Systemic administration of the cytokine interleukin-1 (IL-1) results in increased secretion of ACTH and corticosterone in rats. The available evidence suggests that the acute effects of IL-1 are exerted ultimately at the level of the hypothalamus to increase corticotropin-releasing factor (CRF) secretion into the hypophyseal portal circulation, and hence the central drive on the pituitary-adrenal system. However, the route(s) and mechanism(s) by which circulating IL-1 gains access to central mechanisms governing pituitary-adrenal output remain poorly understood. In this study, we show that intravenous injection of IL-1 beta provokes time- and dose-dependent increases in the expression of the immediate-early gene c-fos, in identified CRF and oxytocin-producing cells of the paraventricular nucleus of the hypothalamus (PVH). Several cell groups known to be involved in central visceromotor regulation also displayed comparable time- and dose-related activation to systemic IL-1, including the bed nucleus of the stria terminalis, the central nucleus of the amygdala, the lateral parabrachial nucleus, and cell groups of the dorsomedial and ventrolateral medulla. Activation of circumventricular organs, which have been hypothesized to serve as central monitors of circulating IL-1, required doses roughly an order of magnitude above those required to activate CRF neurons in the PVH. Combined immunohistochemical and retrograde tracing experiments revealed many IL-1-responsive cells in the nucleus of the solitary tract and the ventrolateral medulla to be catecholaminergic and to project to the region of the PVH. Discrete and unilateral interruption of ascending catecholaminergic projections from the medulla attenuated IL-1-stimulated increases in Fos immunoreactivity and CRF mRNA in the PVH on the ipsilateral side. Disruption of descending projections from circumventricular structures associated with the lamina terminalis did not affect IL-1-mediated Fos induction in the PVH. We conclude that medullary catecholaminergic projections to the PVH play either a mediating or a permissive role in the IL-1-induced activation of the central limb of the hypothalamo-pituitary-adrenal axis.

Individual differences in psychoneuroendocrine function play an important role in health and disease. Developmental models postulate that these individual differences evolve through a progressive series of dynamic time-, place- and context-dependent interactions between genes and environments in fetal, infant and adult life. The effects of early experience have longer-lasting and more permanent consequences than those later in life. Experimental studies in animals have provided convincing evidence to support a causal role for stress-related psychoneuroendocrine processes in negatively influencing critical developmental and health outcomes over the life span, and have also offered valuable insights into putative physiological mechanisms. However, the generalizability of these findings from animals to humans may be limited by the existence of large inter-species differences in physiology and the developmental time-line. We have initiated a program of research in behavioral perinatology and conducted studies over the past several years to examine the effects of stress-related psychoneuroendocrine processes in human pregnancy on fetal developmental and health outcomes. Our findings support a significant and independent role for maternal prenatal stress in the etiology of prematurity-related outcomes, and suggest that these effects are mediated, in part, by the maternal-placental-fetal neuroendocrine axis, and specifically by placental corticotropin-releasing hormone. Our findings also suggest that the use of a fetal challenge paradigm offers a novel way to quantify fetal neurobehavioral maturity in utero, and that the maternal environment exerts a significant influence on the fetal neurodevelopmental processes related to recognition, memory and habituation. Finally, our findings provide preliminary evidence to support the notion that the influence of prenatal stress and maternal-placental hormones on the developing fetus may persist after birth, as assessed by measures of temperament and behavioral reactivity in the first few years of postnatal life. A description of this body of work is followed by the elucidation of questions for further research and a discussion of implications for life-span development and health.