The CRF₁ and the CRF₂ receptor mediate recognition memory deficits and vulnerability induced by opiate withdrawal

Highlights

• Drug-naïve CRF₁ or CRF₂ receptor-deficient mice have unaltered recognition memory.

• CRF₁ receptor-deficiency prolongs opiate withdrawal-induced recognition deficits.

• CRF₂ receptor-deficiency shortens opiate withdrawal-induced recognition deficits.

• CRF₁ and CRF₂ receptor-deficiency eliminate opiate withdrawal-induced vulnerability.

Abstract

Opiate use disorders are associated with impaired cognitive function and altered stress-responsive systems. The corticotropin-releasing factor (CRF) system mediates stress responses via CRF₁ and CRF₂ receptors and may be implicated in substance use disorders. However, the specific role for each of the two known CRF receptor subtypes in cognitive impairment induced by opiate administration and withdrawal remains to be elucidated. In the present study, CRF₁−/−, CRF₂−/− and their respective wild-type mice are injected with escalating doses of morphine and cognitive function assessed by the novel object recognition (NOR) memory task throughout relatively long periods of opiate withdrawal. Early (2 days) phases of opiate withdrawal impair NOR memory in wild-type, CRF₁−/− and CRF₂−/− mice. However, the duration of opiate withdrawal-induced NOR memory deficits is prolonged in CRF₁−/− but shortened in CRF₂−/− mice, as compared to their respective wild-type mice, indicating opposite roles for the two CRF receptor subtypes. Nevertheless, following apparent recovery, exposure to an environmental stressor induces the reemergence of NOR memory deficits in long-term opiate-withdrawn wild-type but not CRF₁−/− or CRF₂−/− mice, indicating an essential role for both CRF receptor subtypes in stress vulnerability. These findings bring initial evidence of a complex physiopathological role for the CRF system in cognitive deficits and the long-lasting vulnerability induced by opiate drugs.

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 expression 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 CRF_6-33, 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 CRF_6-33 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.