Bidirectional regulation over the development and expression of loss of control over cocaine intake by the anterior insula

Abstract

Rationale: Increasing evidence suggests that the anterior insular cortex (AIC) plays a major role in cocaine addiction, being implicated in both impaired insight and associated decision-making and also craving and relapse. However, the nature of the involvement of the insula in the development and maintenance of cocaine addiction remains unknown, thereby limiting our understanding of its causal role in addiction. We therefore investigated whether pre- and post-training bilateral lesions of the AIC differentially influenced the development and the expression of the escalation of cocaine self-administration during extended access to the drug.

Methods: In a series of experiments, Sprague Dawley rats received bilateral excitotoxic lesions of the AIC either prior to, or after 3 weeks of training under 12-h extended self-administration conditions, which are known to promote a robust escalation of intake. We also investigated the influence of AIC lesions on anxiety, as measured in an elevated plus maze and sensitivity to conditioned stimuli (CS)- or drug-induced reinstatement of an extinguished instrumental response.

Results: Whereas, post-escalation lesions of the AIC, as anticipated, restored control over cocaine intake and prevented drug-induced reinstatement, pre-training lesions resulted in a facilitation of the development of loss of control with no influence over the acquisition of cocaine self-administration or anxiety.

Conclusions: AIC lesions differentially affect the development and maintenance of the loss of control over cocaine intake, suggesting that the nature of the contribution of cocaine-associated interoceptive mechanisms changes over the course of escalation and may represent an important component of addiction.

Keywords: Addiction; Anterior insula; Cocaine; Escalation.

Fig. 1

Timeline of the experiments. All rats were habituated to the animal facility for a week during which they were handled and weighed daily. In experiment 1, rats subsequently underwent intrajugular catheterisation (IV surgery), and, after a week of recovery, were trained to acquire cocaine self-administration (SA) over seven daily 1-h sessions under Fixed ratio 1 schedule of reinforcement (FR1). Subsequently, the duration of daily sessions was increased to 12 h wherein all task parameters remained the same. Rats in experiment 1 were exposed to 13 of these sessions, e.g. until a robust and sustained escalation of intake was observed, and subsequently received either sham or bilateral excitotoxic lesions of the AIC. After at least 10 days of recovery, they were then trained again for eight 8 days under extended access conditions prior to be tested in an extinction reinstatement procedure. In experiment 2, rats received either sham or bilateral excitotoxic lesions of the AIC and were given at least 10 days of postoperative recovery prior to be tested for their anxiety in the elevated plus maze (EPM). Rats subsequently underwent intrajugular catheterisation and, after a week of recovery, were trained to acquire cocaine SA over five 1-h daily sessions under FR1. They were then exposed to 19 days of extended 12-h self-administration sessions

Fig. 2

Schematic and histological illustration of bilateral anterior insular lesions. a Histological analysis of the extent of bilateral excitotoxic AIC lesions of rats included in experiment 1 (pink shades) and experiment 2 (blue shades). The extent of the lesions was similar between the two independent experiments. Coordinates are relative to the bregma, plates modified from (Paxinos and Watson 1998). b A cresyl violet-stained coronal section of a left AIC lesion (magnification ×6). Red dotted line indicates the lesion boundaries

Fig. 3

Bidirectional influence of anterior insular lesions on the development and the maintenance of escalated cocaine self-administration. a Rats exposed to 12-h daily cocaine self-administration sessions displayed a robust increase in cocaine infusion over time reflecting a loss of control over drug intake [F _12,144 = 44.17, p < .001]. Following sham or bilateral AIC excitotoxic lesions, unlike sham-operated rats that quickly returned to pre-surgery levels, lesioned rats showed a long-lasting decrease in their daily intake, indicative of a restoration of control over cocaine self-administration [* indicates significant (p < 0.05) difference from last pre-surgery day of long access; $$ indicates main effect of surgery group x pre- and post-surgery block interaction F _1,12 = 7.96, p < .02, pη² = .398]. b AIC lesions did not influence instrumental performance under extinction. Likewise, lesioned rats did not differ from sham controls in response to Cs-induced reinstatement of instrumental responding. In contrast, AIC lesions prevented the dose-dependent increase in instrumental responding observed in controls in the first 15 min following non-contingent administration of cocaine [main effect of group x block interaction F3,36 = 3.36, p < .03, pη2 = .218] [# indicates main effect of group x block interaction; *** indicates p < 0.001, post-hoc Newman-Keuls pairwise comparison at the highest dose of cocaine]. c AIC lesion did not influence anxiety as measured as the percentage of time spent, or entries, in the open arms of an elevated plus maze over the course of a 5-min test. d–e In contrast to the restoration of control seen in animals following post-training lesions, pre-training AIC lesions facilitated and exacerbated escalation of cocaine intake as measured as the increase in daily infusions and escalation ratio. [*** indicates group x session interaction p < .01]. f AIC lesions did not influence the acquisition and maintenance of cocaine self-administration under 1-h-short access conditions