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  • After repeated intermittent exposure to a psychostimulant an


    After repeated, intermittent exposure to a psychostimulant an augmentation of drug response to motor activity is commonly observed, a phenomenon known as behavioral sensitization (Kalivas and Stewart, 1991, Steketee and Kalivas, 2011). On the other hand, several reports have pointed out that stress can induce a comparable enhancement of motor activity, which is termed cross-sensitization (Kalivas et al., 1998, Lu et al., 2001). In addition, social defeat induces an increase in the motor activity induced by amphetamine (Covington and Miczek, 2001, Miczek et al., 1999, Miczek et al., 2011, Nikulina et al., 2004) or cocaine (Kikusui et al., 2005, Sasaki et al., 2015) and this phenomenon is related to neuroadaptations in the corticolimbic system of reward and its interaction with stress circuits, modulated by the CRF hormone (Haass-Koffler and Bartlett, 2012). Our results confirmed the development of a locomotor sensitization response to cocaine and cross-sensitization with RSD were observed. The group of defeated animals pretreated with saline showed a stronger motor response to cocaine than saline-treated controls. In addition, sensitization to cocaine was stronger in cocaine-treated defeated animals. Although the highest dose of the corticotropin-releasing factor CRF1 receptor antagonist CP-154,526 did not block cocaine-induced sensitization, blockade of corticotropin-releasing factor CRF1 receptors significantly reduced cross-sensitization in socially defeated animals. Therefore, corticotropin-releasing factor CRF1 receptor antagonist blocked the response induced by RSD, similarly to that observed with the CPP procedure. In a previous work, Giardino and co-workers (Giardino et al., 2012) showed that genetic deletion or pharmacological blockade of corticotropin-releasing factor CRF1 receptor decreased the locomotor response to cocaine, although not to methamphetamine. In agreement with our results, Boyson and co-workers (Boyson et al., 2011) administered a corticotropin-releasing factor CRF1 receptor antagonist into the ventral tegmental area before social stress and obtained a dose-dependent reduction of stress-induced locomotor sensitization to an acute cocaine challenge. On the contrary, the blockade of peripheral corticotropin-releasing factor CRF2 receptors before each social defeat produced the opposite effects on CPP and locomotor sensitization procedures depending on the dose employed. As Astressin2-B is a peptidic antagonist it does not cross the blood LY364947 receptor barrier; it exerts its effects by specifically blocking pituitary CRF and peripheral receptors located in the heart, skeletal muscle, circulatory system and gastrointestinal tract (Hauger et al., 2006). Rivier and co-workers described that peripheral blockade of corticotropin-releasing factor CRF2 receptors with Astressin2-B in areas non protected by blood brain barrier modulate ACTH release after stress (Rivier et al., 2003). We found that 30 μg/kg of Astressin2-B induced by itself a comparable effect and potentiated the RSD stress on the CPP induced by cocaine. Both socially defeated and non-stressed mice treated with this corticotropin-releasing factor CRF2 receptor antagonist developed preference to the cocaine-paired compartment. On the other hand, the lower dose of Astressin2-B did not modify the effect of RSD on cocaine-induced CPP and did not induce any response in the non-stressed group. Related to locomotor sensitization, no effect was obtained in Astressin2-B pretreated mice. These animals showed cross-sensitization and developed cocaine sensitization, similarly to defeated mice pretreated with saline. There are few studies targeting cocaine and corticotropin-releasing factor CRF2 receptor. Boyson and co-workers (Boyson et al., 2014) found that administration of Astressin2-B directly into the ventral tegmental area 20 min before social defeat reversed the escalation and sensitization to dopamine release in the nucleus accumbens shell induced by cocaine. Equally, administration of another corticotropin-releasing factor CRF2 receptor antagonist, anti-sauvagine-30, into the ventral tegmental area has been shown to block reinstatement of cocaine self-administration after physical stress (Wang et al., 2007). These results contrast with our findings, as we have observed that pretreatment with Atressin2-B enhances the effects of social stress on drug behavior. The different routes of administration of the corticotropin-releasing factor CRF2 receptor antagonists (central ventral tegmental area vs peripherally) and variations in the stress procedure used could explain these divergent results. In the same line of our results, several researchers have reported that knockout corticotropin-releasing factor corticotropin-releasing factor CRF2 receptor mice have higher adrenocorticotropic-hormone and corticosterone levels in the blood due to hypersensitivity of the stress system (Bale et al., 2000, Bale and Vale, 2004, Logrip et al., 2011, Rivier et al., 2003), and that these mice display anxiety behavior in the EPM and open field (Wang et al., 2007). All of these findings point to a complex modulation of the stress response by CRF2 receptor. One of the mechanisms through which antagonism of the CRF2 extraneural receptors induced stressful responses in our study could be the inhibition of CRF release. Rivier and co-workers (Rivier and Rivier, 2014) observed that peripheral injection of Astressin2-B slightly decreased CRF-induced ACTH release. Several authors have speculated that the corticotropin-releasing factor CRF2 receptor acts as a pre-synaptic autoreceptor, inhibiting the release of CRF, which would, in turn, lead to decreased activation of the corticotropin-releasing factor CRF1 receptor (Valdez, 2009). Reul and Holsboer (Reul and Holsboer, 2002) hypothesized that this receptor plays a dual role of activation and inhibition of the stress response. On the one hand, the effect may be modulated by the moment at which the response takes place and by the location of the structure containing the receptor. Activation of corticotropin-releasing factor CRF2 receptor induces an anxiogenic effect in the early phases of the response and an anxiolytic effect in the recuperation phase, thus antagonizing the effects of corticotropin-releasing factor CRF1 receptor in structures like the paraventricular nucleus of hypothalamus, the bed nucleus of the stria-terminalis, the septal nuclei or the amygdala (Rivier et al., 2003).