br Conclusion The results of the present

Conclusion The results of the present study suggest that blockade of CRF1 and CRF2 receptors in the BLA and CeA reduces the duration of TI behavior, probably due to decreased fear and/or anxiety. It is possible that this effect of specific CRF receptor antagonists can occur by reduction of endogenous activation of CRF induced by TI. Further, it was not due to altered spontaneous motor activity, which may non-specifically affect TI behavior. Our findings support the hypothesis that increased activation of CRF receptors, CRF1 and CRF2, in the BLA and CeA is responsible for anxiogenic and fearful responses.
Author contributions
Conflicts of interest
Acknowledgements The authors would like to thank Patrícia Adriana Basile for her technical assistance. This work was supported by CAPES/PROEX, FAPESP (2010/10936-5). R.L. Spinieli is the recipient of a Master’s degree scholarship from CAPES and C.R.A. Leite-Panissi received research grants from the CNPq (# 307383/2012-1).
Introduction Opiate use disorders patients often display impaired cognitive function, especially during drug abstinence periods (APA, 2013). For instance, opiate-abstinent patients perform more poorly than healthy controls on tests measuring episodic memory and executive function, as measured 5 days–3 weeks after the last drug intake (Fishbein et al., 2007, Rapeli et al., 2006). Notably, after the cessation of opiate intake cognitive deficits may persist for relatively longtime periods (APA, 2013), underlie poor treatment compliance and outcome and trigger relapse to opiate drug abuse (Verdejo-Garcia et al., 2004). Accordingly, cognitive dysfunction is found in rodents tested in the eight-arm radial maze and the novel object recognition (NOR) paradigms, both during early (4–14 h) and long-term (6–9 months) opiate withdrawal phases (Rabbani et al., 2009, Sala et al., 1994). Thus, pharmacological remediation of opiate-induced cognitive dysfunction appears as a new strategy for treating opiate use disorders. Opiate withdrawal promotes the activation of the corticotropin-releasing factor (CRF) system, a major coordinator of neuroendocrine and behavioral responses to stressors. For instance, early (8–48 h) morphine withdrawal is associated with increased CRF mRNA entospletinib sale in the central nucleus of the amygdala (CeA) and the paraventricular nucleus of the hypothalamus (PVN), brain regions implicated in the effects of substances of abuse (Ingallinesi et al., 2012, Maj et al., 2003, Papaleo et al., 2007). The biological actions of CRF-like peptides are modulated by a CRF-binding protein (CRF-BP), which is highly conserved in mammalian species (Seasholtz et al., 2002). Studies show a role for the CRF-BP in the effects of substances of abuse. Indeed, administration into the ventral tegmental area (VTA) of CRF6-33, a CRF fragment that competes for the CRF binding site on the CRF-BP, reduces the reinstatement of cocaine-seeking behavior elicited by CRF or UCN I in rats (Wang et al., 2007). Moreover, intra-VTA administration of CRF6-33 reduces ethanol binge drinking in mice (Albrechet-Souza et al., 2015). In mammals, CRF signaling is mediated through two distinct receptors named CRF1 and CRF2 (Hauger et al., 2003). Initial studies using pharmacological agents show that CRF receptor antagonism attenuates either the somatic signs or the negative affective-like states of naloxone-precipitated opiate withdrawal (Heinrichs et al., 1995, Iredale et al., 2000, Lu et al., 2000, Stinus et al., 2005). However, more recent studies using genetic mouse models bearing a targeted inactivation of only one CRF receptor subtype show opposite roles for the CRF1 and the CRF2 receptor in the somatic expression of opiate withdrawal. Indeed, CRF1 receptor-deficiency exacerbates whereas CRF2 receptor-deficiency reduces the somatic signs of opiate withdrawal, as compared to wild-type mice (Papaleo et al., 2008, Papaleo et al., 2007). Moreover, despite either CRF1 or CRF2 receptor-deficiency abolishes the negative affective-like states of opiate withdrawal, CRF1−/− mice show impaired whereas CRF2−/− mice show unaltered ability to cope with the stressful condition of opiate withdrawal (Contarino and Papaleo, 2005, Ingallinesi et al., 2012, Papaleo et al., 2007). Thus, the latter studies indicate that the two known CRF receptor subtypes may have distinct or opposite roles in the behavioral effects of opiate administration and withdrawal. However, the relative contribution of the CRF1 or the CRF2 receptor subtype to cognitive dysfunction and the long-lasting vulnerability to stressful events following opiate withdrawal remains poorly understood.