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  • CCT245737 The physiological role of the UCNs in the


    The physiological role of the UCNs in the regulation of the HPA axis is still under debate (Fekete and Zorrilla, 2007, Suda et al., 2004). UCN 1 was proved to increase the plasma ACTH and corticosterone levels in rats (Bagosi et al., 2014, Vaughan et al., 1995), whereas UCN 2 and UCN 3 were shown to induce or not to induce such a stimulatory effect, depending on the species or the strains being administered (Jamieson et al., 2006, Maruyama et al., 2007, Pelleymounter et al., 2004). In contrast, mice deficient for CRF2 receptors displayed signs of anxiety and depression and increased HPA axis activity, suggesting a possible inhibitory action of CRF2 agonists (Bale et al., 2000, Bale et al., 2002, Bale and Vale, 2003). However, our previous experiments suggest that the role of CRF2 receptor in the regulation of the HPA axis can be inhibitory or stimulatory, depending on the actual concentration of their agonists (Bagosi et al., 2013). Thus, the concentration of UCN 2 and UCN 3 used in the present experiments were chosen based on previous experiments in which 2µl/2µl of UCN 2 and UCN 3 reduced efficiently the plasma ACTH and corticosterone levels in both Wistar rats and CFLP mice, but the data will be revealed in a future study of ours. The present study completes previous studies suggesting that selective CRF2 receptor agonists could be used as a therapy in nicotine addiction. The potential therapeutic role of CRF-related peptides in drug addiction has been proposed earlier. For example, previous studies have already implicated that blocking CRF1 receptors with selective antagonists might prevent the nicotine withdrawal-induced deficit in CCT245737 reward function and stress-induced relapse (Bruijnzeel et al., 2007, Bruijnzeel et al., 2009, Bruijnzeel, 2012, Bruijnzeel et al., 2012, George et al., 2007). Also, previous studies have insinuated that stimulating CRF2 receptor with selective agonists could reduce the alcohol withdrawal-induced anxiety- or depression-like behavior and alcohol-self administration (Valdez et al., 2004, Valdez, 2009). Although this is the first study to demonstrate that central administration of UCN 2 and UCN 3 ameliorates the anxiety- and depression-like signs developed during chronic nicotine treatment and consequent acute withdrawal, and the hyperactivity of the HPA axis that is associated to them.
    Experimental procedures
    Introduction The neurobiology of stress-related mood disorders and related anxiety disorders has been extensively studied over the last decades to develop new strategies and effective therapeutic approaches to psychiatric diseases (Catena-Dell’Osso et al., 2013, Kormos and Gaszner, 2013). However, limited understanding of the pathophysiology of emotional disorders affects the development of novel therapeutic drugs (Catena-Dell’Osso et al., 2013). Thus, the progression of basic research with respect to the neurobiological mechanisms involved in mood disorders and anxiety is critical to support the development of reliable approaches. Since corticotropin-releasing factor (CRF) was isolated and characterized as the major physiological regulator of the hypothalamus-pituitary-adrenal gland axis and was shown to be responsible for the coordination of the endocrine, autonomic and behavioral responses associated with stress (Vale et al., 1981), this neuropeptide has become a potential target for the treatment of stress-related mood disorders (Kormos and Gaszner, 2013). Although the highest concentration of CRF is found in the hypothalamus (Bittencourt and Sawchenko, 2000), this peptide is widely distributed within the central nervous system, including limbic areas (Cummings et al., 1983), which reinforces its involvement in the modulation of emotional responses (Anthony et al., 2014, Donatti and Leite-Panissi, 2011, Henry et al., 2006, Klemm, 2001, Radulovic et al., 1999). In particular, the central nucleus of the amygdala has one of the highest densities of CRF-immunoreactive neurons in the brain (Cummings et al., 1983, Palkovits et al., 1985, Swanson et al., 1983). The CRF neuropeptide exerts its biological activity by binding to two types of CRF receptors, CRF1 and CRF2 receptors (Hauger et al., 2006). More specifically, whereas a high density of CRF1 receptors is found in the anterior lobe of the pituitary, neocortex, hippocampus, basolateral nucleus of the amygdala and brainstem (Potter et al., 1994, Sánchez et al., 1999), CRF2 receptor expression is more restricted to subcortical structures, including the hypothalamus, amygdala, and brainstem (Lovenberg et al., 1995).