br Conclusions Taken together a distinct
Conclusions Taken together, a distinct contrast is observed between ERK1/2 phosphorylation in hypothalamic and extra-hypothalamic AZD1152 regions. The hypothalamus is the only brain region where ERK1/2 phosphorylation was increased 15minutes after the OF stressor. In SD rats CRFR1 expression was decreased two hours after the stressor, a response which may be important in its capacity to cope more effectively with stressful stimuli than WKY rats. The frontal cortex and hippocampus also displayed strain differences in stress-induced changes in CRF receptors. Thus, altered molecular expression of CRFR1 in hypothalamic and extrahypothalamic brain regions following stress exposure may contribute to the aberrant stress response characteristic of WKY rats.
Conflict of interest The Alimentary Pharmabiotic Centre is a research center funded by Science Foundation Ireland (SFI), through the Irish Government's National Development Plan. The authors and their work were supported by SFI (grant nos. 02/CE/B124 and 07/CE/B1368).
Introduction Corticotropin-releasing factor (CRF) and cholecystokinin (CCK), which are two highly colocalized neuropeptides in the brain, have been implicated in the etiology of stress-related anxiety disorders (Bradwejn, 1993, Smoller et al., 2005, Sherrin et al., 2009). CCK was first identified and characterized in the gastrointestinal tract as a hormone and later was found to be one of the most abundant neuropeptides in the brain with high concentrations in the cortex and limbic brain regions (Beinfeld et al., 1981, Beinfeld and Palkovits, 1982). CCK has been linked to anxiety and panic disorders, but also has a role in satiety, learning and memory, thermoregulation, dependence and withdrawal processes (Harro, 2006, Rotzinger and Vaccarino, 2003, Wang et al., 2005). Thus far, the actions of CCK have been attributed to two types of receptor, CCK1 and CCK2 (formerly known as CCK-A and CCK-B, respectively). CCK1 is mainly found in the digestive system, whereas CCK2 receptors are the predominant subtype found in the central nervous system (CNS) and have been implicated in the experimentally induced anxiety and fear in rodents (Farook et al., 2001, Farook et al., 2004, Wang et al., 2003a, Wang et al., 2003b) and panic attacks in humans (Bradwejn and Koszycki, 1994). The effects of stress on CCK neuronal system have been studied in the last three decades. Siegel et al. (1984) demonstrated that CCK concentrations in the prefrontal cortex and the medial and lateral septum were increased after 30min of foot-shock stress exposure. A study on marathon runners suggested that CCK is an important regulation factor in response to anticipatory stress, indicated by the higher level under pre-run conditions than control conditions and the highest after run (Philipp et al., 1992). Later, the effect of 30-min immobilization on the marked increase in cortical CCK-like material release in rats was also demonstrated (Nevo et al., 1996). So far, extensive studies have been carried out on the involvement of the CCKergic system in anxiety-, panic- and stress-related behaviors. Moreover, the functional relationship between CCK and the hypothalamic–pituitary–adrenal (HPA) axis, which is believed to be sensitized after exposure to certain stressors, was also investigated (Bhatnagar et al., 2000, Cournil et al., 2000). CRF, as a major hormone and neurotransmitter in HPA axis, has been accepted as the main neuropeptide involved in both physical and emotional stress (Spiess et al., 1981, Vale et al., 1981). CRF functions as the prime mediator in stress-induced HPA axis activation by triggering the immediate release of ACTH from the anterior pituitary. Subsequently, ACTH stimulates corticosterone release from the zona fasciculate of the adrenal cortex. Two CRF receptors, CRF1 and CRF2, have been identified in the mouse. CRF1 receptor has been hypothesized to be widely expressed in mammalian brain and pituitary and well involved in anxiety behavior (Sanchez et al., 1999). Centrally administered CRF was shown to produce several signs of increased anxiety and transgenic mice that over-express CRF exhibit increased anxiogenic behavior (Stenzel-Poore et al., 1994). Conversely, central administration of either a CRF antisense oligodeoxynucleotide or a CRF receptor antagonist produced anxiolytic effects in the rat (Skutella et al., 1994). These data indicated an increase in anxiety-like behavior after the activation of CRF1 receptor.