Opiate withdrawal promotes the activation of the corticotrop
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 expression in the central nucleus of the amygdala (CeA) and the paraventricular nucleus of the hypothalamus (PVN), Palomid 529 clinical 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.
Thus, in the present study CRF1 and CRF2 receptor-deficient mice are used to assess the specific role for each of the two known CRF receptor subtypes in opiate withdrawal-induced cognitive dysfunction. For this purpose, the NOR task, a paradigm commonly employed to examine recognition memory in rodents, is used (Bevins and Besheer, 2006). The NOR task is based on the innate tendency of rodents to explore more a novel than a familiar object, which per se are devoid of reinforcing properties, making it suitable to specifically monitor cognitive function in substance-treated and/or -withdrawn animals showing altered motivational processes (Barr and Phillips, 1999, Rouibi and Contarino, 2012). Thus, the effect of either CRF1 or CRF2 receptor-deficiency upon NOR memory is first examined in drug-naive mice. Then, studies investigate whether the genetic inactivation of only one CRF receptor subtype affects NOR memory deficits induced by withdrawal from intermittent injections of escalating morphine doses. Moreover, following apparent recovery from the opiate withdrawal-induced NOR memory dysfunction, the implication of the CRF1 and the CRF2 receptor in the stress-induced reemergence of recognition memory deficits is assessed relatively longtime after the cessation of morphine administration.