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  • Our results also showed that the highest dose of


    Our results also showed that the highest dose of Astressin2-B increased the rewarding effects of cocaine, since non-defeated animals treated with this dose developed CPP with a sub-threshold dose. We monitored the acute effects of 30 µg/kg of Astressin2-B and found an increase of anxiety in the open field and EPM tests, an effect that was augmented by previous experience of social stress. It should be kept in mind that these tests took place after the end of the CPP procedure, which confirms that social stress induces long-lasting changes in the mouse brain. Although these effects could be interpreted as a stress response, previous reports have shown that Astressin2-B does not promote anxiogenic-like behavior when administered centrally (Zorrilla et al., 2013). More experimental work is needed to clarify the effects of Astressin2-B. Finally, when analyzing the results obtained in our study, we must take into consideration that the non-peptidic corticotropin-releasing factor CRF1 receptor antagonist CP-154,526 is capable of crossing the blood Chloramphenicol barrier and therefore can block corticotropin-releasing factor CRF1 receptors in all locations, central and peripherally. On the other hand, the corticotropin-releasing factor CRF2 antagonist Astressin2-B is a peptidic compound that does not cross the BBB and therefore blocks only peripheral CRF2 receptors. Importantly, CP-154,526 can block corticotropin-releasing factor CRF1 receptors in the nucleus accumbens or ventral tegmental area; this is not the case for the corticotropin-releasing factor CRF2 antagonist, which only blocks peripheral receptors such as those located in the pituitary. These different profiles of blockade should be considered when interpreting the results.
    Conclusions In conclusion, our results confirm that central corticotropin-releasing factor CRF1 receptors and corticotropin-releasing factor CRF2 receptors in areas no protected by blood brain barrier, like pituitary, differentially modulate the effects of social stress on reward and locomotion induced by cocaine. Therefore, these receptors should be considered potential therapeutic targets for evaluation by research about the treatment of addiction.
    Acknowledgements This work was supported by Ministerio de Economía y Competitividad (MINECO), Dirección General de Investigación [grant number PSI2014-51847-R and PSI2017-83023-R]. Instituto de Salud Carlos III, Red de Trastornos Adictivos (RTA) RD12/0028/0005 y RD16/0017/0007 and Unión Europea, Fondos FEDER “una manera de hacer Europauto. We wish to thank Brian Normanly for his English language editing.
    Introduction Among the several neurotransmitter systems that have been shown to play a role in the modulation of defensive responses elicited by aversive stimuli, the neuropeptide corticotropin-releasing factor or hormone (CRF or CRH) has been attracting the interest of several researchers (e.g., Baldwin et al., 1991, Berridge and Dunn, 1989, Carvalho-Netto et al., 2007, Litvin et al., 2007, Stenzel-Poore et al., 1994). Besides its well-known action on the hypothalamo–pituitary–adrenal (HPA) axis, CRF also acts in other brain areas such as amygdala (Carrasco and Van Der Kar, 2003, Shekhar et al., 2005), bed nucleus of stria terminalis (Sahuque et al., 2006), locus coeruleus (Chen et al., 1992), dorsal raphe nucleus (Carrasco and Van Der Kar, 2003) and the midbrain periaqueductal gray (PAG) (Borelli and Brandão, 2008, Martins et al., 1997, Miguel and Nunes-de-Souza, 2011), increasing anxiety-like responses in various animal tests. The medial prefrontal cortex (mPFC) is also a limbic structure markedly involved in the modulation of defensive reactions (Schwabe et al., 2006, Shah and Treit, 2003). Although there are few studies in the literature investigating the role of CRF within the mPFC in the modulation of defensive reaction, some findings have indicated that this neuropeptide exerts a stimulatory influence on anxiety-related behavior in rats subjected to both acute and chronic restraint stress (Jaferi and Bhatnagar, 2007) and elicits anxiogenic-like behavior in rats exposed to the startle test (Bijlsma et al., 2011). However, opposing effects of CRF in the modulation of anxiety-like behavior have also been reported. For instance, Ohata and Shibasaki (2011) showed that intra-mPFC injections of low doses of this peptide resulted in an anxiogenic-like effect while high doses produced the opposite effect, i.e., anxiety attenuation. Evidence that CRF reduces (rather than increases) anxiety have been reported recently by Pentkowski et al. (2013), who observed that the activation of CRF type 1 (CRF1) receptor within the mPFC attenuates defensive behavior in mice exposed to a predator.