The Dorsal Agranular Insular Cortex Regulates the Cued Reinstatement of Cocaine-Seeking,but not Food-Seeking,Behavior in Rats

Prior studies suggest that the insular cortex (IC), and particularly its posterior region (the PIc), is involved in nicotine craving and relapse in humans and rodents. The present experiments were conducted to determine whether the IC and its different subregions regulate relapse to cocaine-seeking behavior in rats. To address this issue, male Sprague–Dawley rats underwent cocaine self-administration followed by extinction training and reinstatement tests. Before each reinstatement, the PIc or the more anterior dorsal agranular IC (AId) was inactivated to determine their roles in the reinstatement to cocaine seeking. In contrast to the nicotine findings, PIc inactivation had no effect on cue-induced reinstatement for cocaine seeking. However, AId inactivation reduced cued reinstatement while having no effect on cocaine-prime reinstatement. AId inactivation had no effect on reinstatement of food-seeking behavior induced by cues, a food-prime, or cues+food-prime. Based on previous work hypothesizing a role for corticotropin-releasing factor (CRF) in the IC during craving and relapse, a subsequent experiment found that CRF receptor-1 (CRF1) blockade in the AId similarly reduced cued reinstatement. Our results suggest that the AId, along with CRF1 receptors in this region, regulates reinstatement to cocaine seeking, but not food seeking, depending on the type of reinstatement, whereas PIc activity does not influence cue-induced reinstatement.Studies examining the reinstatement of cocaine-seeking behavior have found that the medial prefrontal cortex (PFC) is a critical driver of such behavior (LaLumiere et al, 2012; McFarland et al, 2003), yet considerably less attention has focused on the roles of the lateral PFC in regulating cocaine seeking. However, recent work suggests that the insular cortex (IC), a region in the lateral PFC, may be critically involved in craving and relapse (Naqvi and Bechara, 2010). Human neuroimaging studies have consistently found that drug-associated cues elicit IC activity in participants across multiple types of drug addiction (Brody et al, 2002; Kilts et al, 2004; Myrick et al, 2004). These observations led to a study demonstrating that insula lesions in humans produce significant disruption in nicotine addiction (Naqvi et al, 2007), a finding that has been confirmed in subsequent research (Gaznick et al, 2014) and has led to increased attention to this region with regard to its role in addiction.Experiments using rodent models indicate that reversible inactivation of an IC subregion known as the posterior IC (PIc; also known as the granular IC), as well as electrical stimulation of the IC, reduces both nicotine self-administration and reinstatement in rats (Forget et al, 2010; Pushparaj et al, 2013). In contrast, the more anterior subregions of the IC, including the anterior dorsal agranular IC (AId), appear to drive amphetamine place preference (Contreras et al, 2012). Although the role of the IC has not been extensively investigated with regard to cocaine-seeking behavior, prior work has found that cocaine self-administration increases expression levels of the plasticity-associated gene Arc, notably, in the AId (Zavala et al, 2008). Moreover, the AId innervates the nucleus accumbens (NA) core, a structure known to regulate cocaine seeking in rats, supporting a potential role for the AId in cocaine-seeking behavior (McFarland et al, 2003; Voorn et al, 2004). Indeed, previous work found that AId inactivation reduces cocaine seeking during a reinstatement test in which a contextual odor stimulus associated with cocaine was presented with a conditioned light cue (Di Pietro et al, 2006). In contrast, recent work found that lesions of the anterior portion of the IC, including the AId, potentiated cocaine-seeking behaviors when rats underwent forced abstinence and were then reintroduced to the cocaine-seeking context (Pelloux et al, 2013), leaving the role of the IC in the reinstatement of cocaine seeking unclear.It has been argued that the IC regulates relapse to drug use owing to its role in mediating interoceptive cues (Naqvi et al, 2014). A potential key mediator of these interoceptive cues within the IC is corticotropin-releasing factor (CRF; Naqvi and Bechara, 2009), which is expressed throughout the cortex and at relatively high levels in the IC (Sanchez et al, 1999; Van Pett et al, 2000). Indeed, evidence suggests that the central CRF system has a critical role in driving drug addiction and relapse (Koob, 2013; Zorrilla et al, 2014). Nonetheless, despite the potential significance of this issue, the role of the IC, including its different subregions and CRF1 (CRF receptor-1) receptors, has not been extensively examined in the reinstatement of cocaine-seeking behavior. Therefore, the present study investigated whether these two subregions of the IC, the AId and PIc, regulate cue-induced reinstatement, as well as whether blocking CRF1 receptors in the AId influences cocaine-seeking behavior during reinstatement.