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  • GSK2656157 One specific brain region that may


    One specific GSK2656157 region that may be involved in the reduction of anxiety after anti-SVG-30 treatment is the lateral septum which contains a high density of CRF2 receptors [5], [44]. The lateral septum often exhibits increased immediate early gene expression in response to stress and anxiety [14], [40], [50] and a reduction in stress-induced c-fos expression after benzodiazepine treatment [3]. Behavioral studies indicate that infusion of benzodiazepines directly into the lateral septum produces anxiolytic-like effects including an increase in punished drinking [13], a facilitation in open arm exploration in the elevated plus maze [39] and a reduction in defensive burying of an electrified shock prod [39]. In our study, cannulae were placed in the lateral ventricles at the level of the lateral septum in order to increase the likelihood that CRF2 receptors in this brain structure would be antagonized by anti-SVG-30. Support for this possibility comes from another study conducted in our laboratory using identical cannula placements. In that study, we found that administration of a CRF2 antisense oligonucleotide produced a highly significant knockdown of CRF2 receptors in the lateral septum that was accompanied by a significant reduction in freezing [21]. Hypersecretion of brain CRF is associated with a number of disorders including major depression, posttraumatic stress disorder, anorexia nervosa, and alcohol withdrawal [1], [4], [26], [34]. Importantly, increased CRF levels in cerebrospinal fluid of severely depressed individuals decrease after antidepressant treatment [11]. Furthermore, studies conducted in animals have led to the hypothesis that the actions of CRF underlying neuropsychiatric disorders are meditated by the CRF1 receptor, which has implications for the understanding and treatment of diverse clinical disorders [22], [32]. Potential support for this view comes from preclinical pharmacological studies demonstrating that administration of the triazolobenzodiazepine alprazolam reduces brain CRF levels and CRF1 mRNA expression [47]. This finding suggests that the anxiolytic effects of benzodiazepines may be mediated via their effects on CRF systems that involve a reduction in CRF1 receptors. However, alprazolam administration also produced a concurrent increase in urocortin levels and CRF2 mRNA which has implications for an anxiolytic role. Whether increases in urocortin and CRF2 receptors are necessary in conjunction with reductions in CRF concentrations and CRF1 receptors to effectively mediate the anxiolytic effects of alprazolam are not known. Our current work, demonstrating a clear reduction in animal anxiety behavior after administration of a CRF2 antagonist further highlights the possibility that CRF2 receptors may play a significant role in psychopathology. It is possible that a neural system that is activated during stress and anxiety states [7], [41] and composed of diverse brain structures containing CRF1 and/or CRF2 receptors [5], [44] may be dampened by antagonism of either CRF receptor type resulting in an overall reduction in anxiety. That CRF1 and CRF2 receptors may contribute to the expression of anxiety behavior is further revealed by data from a recent study [21]. In that study, CRF2 antisense oligonucleotide treated rats that received a dose of DMP904, a specific CRF1 antagonist [16] showed a further significant reduction in conditioned freezing in comparison to rats treated only with the CRF2 antisense or the CRF1 antagonist.
    Introduction Hypothalamic-pituitary-adrenal (HPA) axis, defensive behavior, autonomic, metabolic, immune, and cardiovascular responses during stress and trauma are coordinated by the interplay of neuronal corticotropin releasing factor (CRF) and urocortin peptides (UCN1, UCN2, UCN3) differentially binding to and activating CRF receptors type 1 (CRF1) and type 2 (CRF2), which are members of the class B1 group of the G protein-coupled receptor (GPCR) superfamily [1], [2], [3], [4], [5], [6], [7]. Both CRF receptors are capable of signaling via the protein kinase A (PKA), protein kinase C (PKC), extracellular signal-regulated kinase (ERK) mitogen-activated protein (MAP) kinase, protein kinase B (Akt), and other pathways, although the dominant mode of signal transduction is coupling to G protein subunit Gsα and activating adenylyl cyclase to generate adenosine 3′,5′-cyclic monophosphate (cyclic AMP) [1], [2], [3], [4], [5], [6], [7]. CRF1 receptor signaling generates critical defensive behaviors, HPA hormone secretion, and physiological responses required to survive trauma and stress [1], [2], [3], [4], [5], [6], [7], [8], [9], [10], [11], [12]. Behavioral actions mediated by the CRF2 receptor are complex and contingent upon the brain site and activating agonist unlike the CRF1 receptor [1], [6], [7], [8], [9]. Emerging evidence indicates, however, that forebrain CRF2 receptor signaling can be anxiogenic depending on the intensity and duration of the stress state [1], [9], [10], [11]. These CRF receptor-mediated processes must be rapidly initiated in order to meet physiological demands essential for survival. Counter-regulation to restore homeostasis is equally important, however, to prevent stress-induced psychiatric and medical illnesses developing from the detrimental effects of abnormal CRF receptor signaling.