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Dysfunction of the neuroendocrine HPA axis is associated with a variety of physiological and psychological pathologies. The authors show that corticotropin-releasing factor type 1 receptors within the hypothalamic paraventricular nucleus are a key central component of HPA axis regulation that prepares the organism for chronic exposure to stressful stimuli. The hypothalamic–pituitary–adrenal axis is a pivotal component of an organism's response to stressful challenges, and dysfunction of this neuroendocrine axis is associated with a variety of physiological and psychological pathologies. We found that corticotropin-releasing factor type 1 receptor within the paraventricular nucleus of the hypothalamus is an important central component of hypothalamic–pituitary–adrenal axis regulation that prepares the organism for successive exposure to stressful stimuli.

Key Points Depending on the brain region involved, local activation of corticotropin-releasing factor receptor 1 (CRFR1) and CRFR2 by their ligands can induce acute anxiolytic or anxiogenic effects. The region-specific modulation of anxiety-like behaviour by CRFR activation depends on the specific cell type in which it is expressed and the neuronal circuit in which it plays a part. The downstream intracellular pathways triggered by CRFR activation are also brain-region specific and depend on the exact ligand–receptor interaction by which they are induced. Local differences in the regulation of CRFR signalling exist, with processes of desensitization being dependent on local expression of its regulators (including G protein-coupled receptor kinases (GRKs) and β-arrestins) and of the binding ligand. Many effects of CRFR activation that are observed at the cellular and behavioural level depend on the individual's current stress level and history of exposure to stress. These dose-dependent effects may be caused by loss of receptor specificity at higher concentrations of available ligand, whereas previous experience modulates receptor sensitivity by regulating receptor internalization or recruitment. Long-lasting activation of CRFRs, for example, through chronic or repeated exposure to stress, can induce effects that are very distinct from their acute effects and seem to involve remodelling of structural plasticity. Corticotropin-releasing factor (CRF) and urocortins have traditionally been proposed to promote stress and stress recovery, respectively. However, recent findings suggest that this view is overly simplistic. Chen and colleagues review evidence showing that CRF-receptor signalling is region- and cell type-specific and influenced by the individual's experience. Dysregulation of the corticotropin-releasing factor (CRF)–urocortin (UCN) system has been implicated in stress-related psychopathologies such as depression and anxiety. It has been proposed that CRF–CRF receptor type 1 (CRFR1) signalling promotes the stress response and anxiety-like behaviour, whereas UCNs and CRFR2 activation mediate stress recovery and the restoration of homeostasis. Recent findings, however, provide clear evidence that this view is overly simplistic. Instead, a more complex picture has emerged that suggests that there are brain region- and cell type-specific effects of CRFR signalling that are influenced by the individual's prior experience and that shape molecular, cellular and ultimately behavioural responses to stressful challenges.

Key Points The search for novel drugs for psychiatric disorders is driven by the growing medical need to improve on the effectiveness and side-effect profile of currently available therapies. The rapid advances in understanding the structure and regulation of genes encoding neuropeptides, the characterization of their receptors, the synthesis of non-peptide receptor ligands and the wealth of animal data have made neuropeptide receptors attractive therapeutic targets for the treatment of psychiatric disorders. However, clinical studies with synthetic neuropeptide ligands have been unable to confirm the promise predicted by animal studies. In this Review, we analyse preclinical and clinical results for neuropeptide receptor ligands that have been studied in clinical trials for psychiatric diseases, including agents that target the receptors for tachykinins, corticotropin-releasing factor, vasopressin and neurotensin, and suggest new ways to exploit the full potential of these candidate drugs. Although drugs targeting neuropeptide receptors have not met their expectations, we do not believe that the whole concept should be considered a failure. Among the most commonly noted reasons for the failure to successfully develop neuropeptide receptor ligands for psychiatric disorders is the poor predictivity of the animal models that have been used to screen these molecules. Drug selection based on data from animal models must be much more stringent and use a variety of models assessing different aspects of the disease. The future development of drugs targeting neuropeptide receptors also has to bear in mind the specificity of their mechanism of action. Genetic tests and biomarkers are needed to identify subgroups of patients in whom a specific neuropeptidergic mechanism accounts for the clinical condition and who would thus be anticipated to benefit from a specific drug intervention. A wealth of preclinical data on the role of neuropeptides in modulating behaviour has encouraged extensive efforts to target neuropeptide receptors for the treatment of psychiatric diseases, but so far clinical studies have not led to marketed drugs. This article analyses research on neuropeptide receptor ligands that have been studied in clinical trials, including agents that target the receptors for tachykinins, corticotropin-releasing factor and vasopressin, and suggests new ways to realize their full potential. The search for novel drugs for treating psychiatric disorders is driven by the growing medical need to improve on the effectiveness and side-effect profile of currently available therapies. Given the wealth of preclinical data supporting the role of neuropeptides in modulating behaviour, pharmaceutical companies have been attempting to target neuropeptide receptors for over two decades. However, clinical studies with synthetic neuropeptide ligands have been unable to confirm the promise predicted by studies in animal models. Here, we analyse preclinical and clinical results for neuropeptide receptor ligands that have been studied in clinical trials for psychiatric diseases, including agents that target the receptors for tachykinins, corticotropin-releasing factor, vasopressin and neurotensin, and suggest new ways to exploit the full potential of these candidate drugs.

Since corticotropin-releasing factor (CRF) was first characterized, a growing family of ligands and receptors has evolved. The mammalian family members include CRF, urocortinI (UcnI), UcnII, and UcnIII, along with two receptors, CRFR1 and CRFR2, and a CRF binding protein. These family members differ in their tissue distribution and pharmacology. Studies have provided evidence supporting an important role of this family in regulation of the endocrine and behavioral responses to stress. Although CRF appears to play a stimulatory role in stress responsivity through activation of CRFR1, specific actions of UcnII and UcnIII on CRFR2 may be important for dampening stress sensitivity. As the only ligand with high affinity for both receptors, UcnI's role may be promiscuous. Regulation of the relative contribution of the two CRF receptors to brain CRF pathways may be essential in coordinating physiological responses to stress. The development of disorders related to heightened stress sensitivity and dysregulation of stress-coping mechanisms appears to involve regulatory mechanisms of CRF family members.

Highly palatable foods and dieting are major contributing factors for the development of compulsive eating in obesity and eating disorders. We previously demonstrated that intermittent access to palatable food results in corticotropin-releasing factor-1 (CRF1) receptor antagonist-reversible behaviors, which include excessive palatable food intake, hypophagia of regular chow, and anxiety-like behavior. However, the brain areas mediating these effects are still unknown. Male Wistar rats were either fed chow continuously for 7 days/week (Chow/Chow group), or fed chow intermittently 5 days/week, followed by a sucrose, palatable diet 2 days/week (Chow/Palatable group). Following chronic diet alternation, the effects of microinfusing the CRF1 receptor antagonist R121919 (0, 0.5, 1.5 μg/side) in the central nucleus of the amygdala (CeA), the basolateral nucleus of the amygdala (BlA), or the bed nucleus of the stria terminalis (BNST) were evaluated on excessive intake of the palatable diet, chow hypophagia, and anxiety-like behavior. Furthermore, CRF immunostaining was evaluated in the brain of diet cycled rats. Intra-CeA R121919 blocked both excessive palatable food intake and anxiety-like behavior in Chow/Palatable rats, without affecting chow hypophagia. Conversely, intra-BlA R121919 reduced the chow hypophagia in Chow/Palatable rats, without affecting excessive palatable food intake or anxiety-like behavior. Intra-BNST treatment had no effect. The treatments did not modify the behavior of Chow/Chow rats. Immunohistochemistry revealed an increased number of CRF-positive cells in CeA--but not in BlA or BNST--of Chow/Palatable rats, during both withdrawal and renewed access to the palatable diet, compared with controls. These results provide functional evidence that the CRF-CRF1 receptor system in CeA and BlA has a differential role in mediating maladaptive behaviors resulting from palatable diet cycling.

There is an extensive evidence that corticotropin releasing factor (CRF) is hypersecreted in depression and anxiety, and blockade of CRF could have therapeutic benefit. We report preclinical data and the results of a clinical Phase I study with the novel nonpeptide CRF 1 antagonist NBI-34041/SB723620. Preclinical data conducted with different cell lines expressing human CRF receptors and in Wistar and Sprague–Dawley rats indicate that NBI-34041 is effective in reducing endocrine responses to pharmacological and behavioral challenge mediated by CRF 1 receptors. These specific properties and its well-documented safety profile enabled a clinical Phase I study with 24 healthy male subjects receiving NBI-34041 (10, 50, or 100 mg) or placebo for 14 days. Regulation of the hypothalamic–pituitary–adrenocortical (HPA) axis was evaluated by intravenous stimulation with 100 μg of human CRF. Psychosocial stress response was investigated with the Trier Social Stress Test (TSST). Treatment with NBI-34041 did not impair diurnal adrenocorticotropic hormone (ACTH) and cortisol secretion or CRF evoked ACTH and cortisol responses but attenuated the neuroendocrine response to psychosocial stress. These results suggest that NBI-34041 is safe and does not impair basal regulation of the HPA system but improves resistance against psychosocial stress. NBI-34041 demonstrates that inhibition of the CRF system is a promising target for drug development against depression and anxiety disorders.

Introduction In addition to their role in regulation of the hypothalamic-pituitary-adrenal-axis, corticotropin-releasing factor (CRF) and its related peptides, the urocortins, are important mediators of physiological and pathophysiological processes of the central nervous, cardiovascular, gastrointestinal, immune, endocrine, reproductive, and skin systems. Altered regulation of CRF-mediated adaptive responses to various stressful stimuli disrupts healthy function and might confer vulnerability to several disorders, including depression and anxiety. Methodology This narrative review was conducted through search and analysis of studies retrieved from online databases using a snowball method. Results This review covers aspects beginning with the discovery of CRF, CRF binding protein and their actions via interaction with CRF receptors type 1 and type 2. These are surface plasma membrane receptors, activation of which is associated with conformational changes and interaction with a variety of G-proteins and signaling pathways. We also reviewed the pharmacology and mechanisms of the receptor signaling modulatory activity of these receptors. Conclusion This review compiles and presents knowledge regarding the CRFergic system, including CRF related peptides, CRF binding protein, and CRF receptors, as well as some evidence that is potentially indicative of the biological roles of these entities in several physiological and pathophysiological processes.

Drug dependence is a chronically relapsing disorder that places an enormous strain on healthcare systems. For treatments to have long-term clinical value, they must address the causes of relapse. Corticotropin-releasing factor (CRF), a neuropeptide central to the stress response, may be one key to solving the relapse cycle. CRF is hypothesized to mediate the elevated anxiety and negative emotional states experienced during the development of dependence. This review summarizes existing data on changes in the CRF system produced by drugs of abuse and the function of CRF receptors in regulating behavioural responses to drugs of abuse, with an emphasis on drug dependence. Drug-induced changes in neuronal excitability throughout the limbic system, as well as the reversal of these neuroadaptations by CRF receptor antagonists, are also addressed. CRF receptor antagonists, by reducing the motivational effects of drug withdrawal and protracted abstinence, are proposed to be novel therapeutic targets for drug abuse and addiction.

Early-life stress, acting through corticotrophin-releasing hormone (CRH) and its receptor CRHR1, can have long-lasting effects on animals' behavior. Nectin-3 is a cell adhesion molecule whose heterodimeric interaction with presynaptic nectin-1 organizes the postsynaptic afadin–actin–N-cadherin complex to shape synaptic structure and function. Here, the authors show that structural synaptic adaptation and cognitive dysfunction in adulthood following early-life stress are dependent on CRH signaling acting through Nectin-3. Stress impairs cognition via corticotropin-releasing hormone receptor 1 (CRHR1), but the molecular link between abnormal CRHR1 signaling and stress-induced cognitive impairments remains unclear. We investigated whether the cell adhesion molecule nectin-3 is required for the effects of CRHR1 on cognition and structural remodeling after early-life stress exposure. Postnatally stressed adult mice had decreased hippocampal nectin-3 levels, which could be attenuated by CRHR1 inactivation and mimicked by corticotropin-releasing hormone (CRH) overexpression in forebrain neurons. Acute stress dynamically reduced hippocampal nectin-3 levels, which involved CRH-CRHR1, but not glucocorticoid receptor, signaling. Suppression of hippocampal nectin-3 caused spatial memory deficits and dendritic spine loss, whereas enhancing hippocampal nectin-3 expression rescued the detrimental effects of early-life stress on memory and spine density in adulthood. Our findings suggest that hippocampal nectin-3 is necessary for the effects of stress on memory and structural plasticity and indicate that the CRH-CRHR1 system interacts with the nectin-afadin complex to mediate such effects.

The interplay of environmental and genetic factors in the developmental organization of the hippocampus has not been fully elucidated. The neuropeptide corticotropin-releasing factor (CRF) is released from hippocampal interneurons by environmental signals, including stress, to increase synaptic efficacy. In the early postnatal hippocampus, we have previously characterized a transient population of CRF-expressing Cajal-Retzius-like cells. Here we queried whether this stress-activated neuromodulator influences connectivity in the developing hippocampal network. Using mice deficient in the principal hippocampal CRF receptor [ CRF1(-/-)] and organotypic cultures grown in the presence of synthetic CRF, or CRF receptor antagonists, we found robust effects of CRF on dendritic differentiation in hippocampal neurons. In CRF1(-/-) mice, the dendritic trees of hippocampal principal cells were exuberant, an effect that was induced in normal hippocampi in vitro by the presence of CRF1 antagonists. In both cases, total dendritic length and dendritic branching were significantly increased. In contrast, exogenous synthetic CRF blunted the dendritic growth in hippocampal organotypic cultures. Taken together, these findings suggest that endogenous CRF, if released excessively by previous early postnatal stress, might influence neuronal connectivity and thus function of the immature hippocampus.