Rachel Yehuda

Psychiatry Department and Division of Traumatic Stress Studies, Mount Sinai, School of Medicine and Bronx Veterans Affairs, Bronx, NY, USA Abstract This chapter discusses how neuroendocrine findings in posttraumatic stress disorder (PTSD) potentially inform us about hypothalamic -pituitary-adrenal (HPA) alterations in PTSD and highlight alterations relevant to the identification of targets for drug development. The majority of studies demonstrate alterations consistent with an enhanced negative...

CRF type 1 receptor knockout mice CRF receptor KO

CRF, receptor KO mice were generated by two independent groups using targeted gene inactivation in embryonic stem cells (Smith et al., 1998 Timpl et al., 1998). These two lines of mice generally show similar phenotypes despite differences in the genetic background of the embryonic stem cell lineage. Most notably, these mice display severe alterations in HPA axis regulation and marked glucocorticoid deficiency, along with impaired initiation of behavioral responses to stress. Basal HP A axis...

Jeffrey A Lieberman2

1 Duke University School of Medicine and Durham VAMC, Durham, NC 27705, USA -UNC-Chape Hill School of Medicine, Chapel Hill, NC 27599, USA 3Vanderbilt University School of Medicine, Psychiatric Hospital at Vanderbilt, Suite 313, 1601 23rd Avenue South, Nashville, TN 37218, USA Abstract Both preclinical and clinical evidence suggest that atypical antipsychotics may modulate the stress response in a manner that is distinct from conventional agents. For example, atypical antipsychotics have...

Info

Corticosterone response to restraint stress (adapted from Tamashiro et al, 2004). CON, control DOM, dominant SRS, stress-responsive subordinate NRS, stress nonresponsive subordinates. Thus, the decreased activity of the HPA axis in stress nonresponsive subordinates may be the combined result of enhanced inhibitory input into the PVN due to increased glucocorticoid feedback or to increased inhibitory neural input (Herman et al., 1996). Preliminary data suggest that forebrain GABAergic...

Christopher R Pryce Daniela Riiedi Bettschen Andrea C Dettling and Joram Feldon

Behavioural Neurobiology Laboratory, Swiss Federal Institute of Technology Zurich, Schorenstrasse 16, Abstract Depression is now one of the most common human illnesses and is of immense clinical and economic importance. Considerable preclinical research efforts have been made to establish animal models of depression, and more recently the human evidence derived from brain imaging studies has provided important insights into the functional neuroanatomical correlates of depression. Despite this,...

CRFoverexpressing transgenic mice CRFTg

We created a transgenic model of chronic CRF hypersecretion (CRF-Tg mice) using a chimeric CRF transgene comprised of the metallothionein promoter linked to the rat CRF genomic gene (Stenzel-Poore et al., 1992). These mice exhibit chronic HPA axis activation due to central overproduction of CRF. Basal ACTH is elevated two- to five-fold, resulting in a tenfold elevation in circulating glucocorticoids. Physically, such high corticosterone levels render these mice Cushingoid. By eight weeks of...

Dysregulation of CRF pathways in human disease states

Imbalances of the HPA axis and central CRF pathways have been associated with allostatic load and subsequent pathological states (Schulkin et al., 1998). In the periphery, excess circulating glucocorticoids caused by prolonged activation of the HPA axis or long-term treatment with exogenous glucocorticoids results in Cushing's disease or syndrome (Nelson, 1989). Continued exposure to high levels of glucocorticoids eventually leads to metabolic dysfunction that may include muscle wasting,...

CRF knockout mice CRF KO

Mice deficient in CRF were created using targeted gene inactivation in embryonic stem cells (Muglia et al., 1995). This model has added important information to our present understanding of CRF roles and in some cases has provided evidence that contradicts current hypotheses. CRF KO mice exhibit severe glucocorticoid deficiency and impaired HPA axis activation - features predicted to occur in the absence of CRF. Effects of CRF absence on organ development and longevity Histological examination...

Ptsd

Brief one-time exposure produces long-term effects. Produces conditioned fear responses. Characterized by time-dependent sensitization. Produces enhanced HPA negative feedback. Produces a sustained exaggeration of the acoustic startle response. Exposed animals can be divided into well-adapted and mal-adapted. Single episode can produce sustained behavioral inhibition, perhaps reflective of PTSD-like avoidance. Produces sensitization of LC-noradrenaline neurons. Produces short-term...

Cytokine activation of the hypothalamopituitaryadrenal axis

Crf Hpa Axis

Department of Pharmacology and Therapeutics, Louisiana State University Health Sciences Center. P.O. Box 33932. Shreveport. LA 71103-3932, USA Abstract The discovery that peripheral administration of interleukin-1 (IL-1) to rats potently activated the hypothalamo-pituitary-adrenocortical (HPA) axis, initiated a new understanding of the interactions between the immune system and the brain. It was proposed, and widely accepted that the increase in circulating concentrations of glucocorticoids...

Glucocorticoid receptor antisense knock down

Partial knock-down and tissue-specific mutations of the glucocorticoid receptor have circumvented perinatal mortality and allowed for examination of glucocorticoid pathways in adult physiology. Pepin et al. (1992) created a transgenic mouse model that harbors a transgene that constitutively expresses antisense RNA against GR. To restrict transgene expression to the CNS, a neurofilament promoter was used. Thus, antisense expression impairs production of GR mRNA predominantly in neural tissue,...

Nonpeptide vasopressin Vlb receptor antagonists

Guy Griebel1'* and Claudine Serradeil-Le Gal2 ' Sanofi-Synthelabo Recherche, Bagneux, France 2 Sanofi-Synthelabo Recherche, Toulouse, France Abstract Arginine vasopressin (AVP) is critical for adaptation of the hypothalamo-pituitary-adrenal axis during stress through its ability to potentiate the stimulatory effect of CRF. This observation, taken together with the identification of AVP receptors (e.g. V(b) in limbic structures has led to the idea that this peptide may provide a good opportunity...

Glucocorticoid antagonists and depression

Hpa Dysfunction

NeurAxon Inc., Suite 318, 16-1375 Southdown Road, Mississauga, ON, Canada L5J 2Z1 Abstract Substantial evidence exists to indicate a prominent role for chronically elevated levels of Cortisol and a dysfunctional feedback system within the hypothalamic-pituitary-adrenal (HPA) axis in major depressive disorder. Chronically elevated Cortisol levels are strongly correlated with depression and normalization of Cortisol levels accompanies recovery failure to normalize predicts relapse or poor...

And Lucianne Groenink12

1 Department of Psyehopharmaeology, Utrecht Institute of Pharmaceutical Sciences, Faculty of Pharmaceutical Sciences, Utrecht University, Sorbonnelaan 16, 3584CA Utrecht, The Netherlands 2Rudolf Magnus Institute of Neuroscience, University Medical Centre Utrecht, Utrecht, The Netherlands 3Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA Abstract When animals are confronted with a stressor, they respond by an extensive stress response, amongst which a rise in body...

Ssr149415

Chemical structures of SSR149415 ((2S, H-indol-3-yl -4-hydroxy-TV, N-dimethyl-2-pyrrolidine carboxamide, isomer(-)). pituitary adrenocorticotropin (ACTH) secretion (McCann and Brobeck, 1954 Antoni, 1993 Aguilera, 1994). AVP is critical for adaptation of the hypothalamo-pituitary adrenal (HPA) axis during stress through its ability to potentiate the stimulatory effect of CRF. Both acute and repeated stresses (e.g., restraint, foot shocks) stimulate release of AVP from the median eminence...

Substance P NKi receptor antagonists

Substance Headache

Clinical Neuroscience, Merck Research Laboratories, BL2-5, West Point, PA 19486, USA Abstract Stress responses involve changes in hormone secretion, respiration, cardiovascular, and gastrointestinal function, and behavior in order to prepare an organism to respond to perceived or actual danger. They are orchestrated by neural circuits including the amygdala, brainstem, and hypothalamus. Substance P is a peptide neurotransmitter that is expressed within these neural pathways and can activate...

CRF type 2 receptor knockout mice CRF2 receptor KO

The role of CRF2 receptor pathways in stress-related pathways remained elusive until the recent generation of CRF2 receptor KO mice and the development of a specific CRF2 receptor antagonist. In addition, the recent discovery of CRF2 receptor-selective ligands, urocortin 2 and urocortin 3, aid greatly in our understanding of CRF2 receptor pathways. CRF2 receptor KO mice were generated by us Coste et al, 2000 and two other independent groups Bale et al, 2000 Kishimoto et al, 2000 using targeted...

Randall R Sakai and Kellie LK Tamashiro

Department of Psychiatry, University of Cincinnati Medical Center, 2170 E. Ga braith Road, Bldg 43 UC-E, Cincinnati, OH 45237, USA The field of stress research has generated growing interest in response to the escalating number of psychopathologies associated with chronic stress in humans. A better understanding of the mechanisms through which chronic stress leads to these pathologies will enhance the development, effectiveness and efficiency of rational clinical therapies. As such, a variety...