br Material and methods br
Material and methods
Discussion The present study shows that peripheral administration of the nonpeptidic corticotropin-releasing factor CRF1 receptor antagonist CP-154,526 before a social defeat inhibits the development of CPP induced with a subthreshold dose of cocaine and reverses the effects of social defeat on motor sensitization. Conversely, the administration of the peptidic corticotropin-releasing factor CRF2 receptor antagonist Astressin2-B exerted the opposite effects to those observed after corticotropin-releasing factor CRF1 receptor blockade. The administration of the corticotropin-releasing factor CRF2 receptor antagonist Astressin2-B induced a stress response comparable to that observed after RSD. This stressing effect of Astressin2-B was confirmed with the open field and EPM procedures. The present results suggest that the long-term effects of RSD on the conditioned rewarding effects of cocaine and the development of motor sensitization depend on central and peripheral CRF receptors. As previously reported, RSD increased the conditioned reinforcing effects of cocaine, as the CPP induced by a non-effective dose of this drug was acquired and reinstated in defeated mice. Equally, the present results confirm that motor sensitization can be induced by repeated pre-treatment with a high dose of cocaine, and that this phenomenon is modulated by stressful life experiences. According to previous research, stress experiences have significant effects on the acquisition, expression, mu receptor antagonist and reinstatement of CPP induced by cocaine (Logrip et al., 2011, Lu et al., 2003, Sanchez and Sorg, 2001). Previous studies in our laboratory have shown that mice exposed to social defeat exhibit a stronger CPP for the cocaine-paired compartment than non-stressed counterparts. Adult mice defeated during adolescence or adulthood developed a preference for the cocaine-paired compartment after being conditioned with a non-effective dose of the drug (1 mg/kg), and showed a reinstated preference after receiving only 0.5 mg/kg of cocaine (Montagud-Romero et al., 2016, Rodríguez‐Arias et al., 2017). Similar results have been observed with alcohol and MDMA (García-Pardo et al., 2015; Rodriguez-Arias et al., 2016). Furthermore social defeat during an agonistic encounter in a neutral area prior to a reinstatement test has been shown to reinstate cocaine CPP in adult mice (Land et al., 2009; Titomanlio et al., 2013) and to increase susceptibility to cocaine-induced reinstatement of CPP (Do Couto et al., 2009). These results suggest that social stress induces sensitization of the reward system that makes mice more sensitive to these drugs. In the present study, we have found that this augmented sensitivity to the conditioned rewarding effects induced by cocaine is modulated by corticotropin-releasing factor CRF1 receptor. At the highest dose (10 mg/kg) the nonpeptidic corticotropin-releasing factor CRF1 receptor antagonist CP-154,526 reversed the effects of social stress on the cocaine-induced CPP, since defeated mice did not develop CPP. While a lower dose (5 mg/kg) of CP-154,526 failed to block this effect (mice developed CPP), no reinstatement was achieved with a priming dose of 0.5 mg/kg, unlike in socially defeated animals pretreated with saline. It has to be taken into consideration that the corticotropin-releasing factor CRF1 receptor antagonist has been dissolved with Tween-80, which has been probed to enhance drug delivery across the blood–brain barrier (Azhari et al., 2016). Although no studies have previously addressed this issue using the CPP and social stress paradigm, Boyson and co-workers (Boyson et al., 2011, Boyson et al., 2014) did observe that another corticotropin-releasing factor CRF1 receptor antagonist (CP-376,395) -administrated peripherally or into the ventral tegmental area- reduced the escalation of cocaine self-administration after social defeat. Other researchers obtained similar results using corticotropin-releasing factor CRF1 receptor antagonists and other kinds of stressors; for instance Shaham and co-workers (Shaham et al., 1998) found that administration of the corticotropin-releasing factor CRF1 receptor antagonist CP-154,526 prior to a physical stressor (footshocks) significantly attenuated the reinstatement of self-administration of cocaine or heroin in trained rats, while Le and co-workers (Lê et al., 2000) also found an attenuation of footshock stress-induced reinstatement of ethanol self-administration. Using the CPP paradigm, Lu and co-workers (Lu et al., 2001) reported that CP-154,526 blocked the reinstatement of cocaine CPP induced by physical stress, but failed to block that induced by a priming dose of the drug.