A Role for the Insular Cortex in Long-Term Memory for Context-Evoked Drug Craving in Rats

Abstract

Drug craving critically depends on the function of the interoceptive insular cortex, and may be triggered by contextual cues. However, the role of the insula in the long-term memory linking context with drug craving remains unknown. Such a memory trace probably resides in some neocortical region, much like other declarative memories. Studies in humans and rats suggest that the insula may include such a region. Rats chronically implanted with bilateral injection cannulae into the high-order rostral agranular insular cortex (RAIC) or the primary interoceptive posterior insula (pIC) were conditioned to prefer the initially aversive compartment of a 2-compartment place preference apparatus by repeatedly pairing it to amphetamine. We found a reversible but long-lasting loss (ca. 24 days) of amphetamineconditioned place preference (CPP) and a decreased expression in the insula of zif268, a crucial protein in memory reconsolidation, when anisomycin (ANI) was microinjected into the RAIC immediately after the reactivation of the conditioned amphetamine/context memory. ANI infusion into the RAIC without reactivation did not change CPP, whereas ANI infusion into pIC plus caused a 15 days loss of CPP. We also found a 24 days loss of CPP when we reversibly inactivated pIC during extinction trials. We interpret these findings as evidence that the insular cortex, including the RAIC, is involved in a context/drug effect association. These results add a drug-related memory function to the insular cortex to the previously found role of the pIC in the perception of craving or malaise.

Brain Regions Affected by Impaired Control Modulate Responses to Alcohol and Smoking Cues

“…Thus, the insula may have a casual role in maintaining dependence through its representation of bodily experiences associated with withdrawal and craving (Naqvi and Bechara, 2009). Furthermore, a rodent study showed that the anterior and posterior regions of the insula play a crucial role in the long-term memory associated with drug use and confi rmed the previously found role of the posterior insula in the perception of drug craving (Contreras et al, 2012). Together, the PCC and posterior insula may infl uence attention and salience functions and regulation of incentive reward and cognitive control, which in turn may infl uence the concurrent use and comorbidity of alcohol and nicotine dependence.…”

Damage to insula abolishes cognitive distortions during simulated gambling

“…Via a similar mechanism, insula activity has been linked to drug craving, such that smokers who suffered infarcts to the insula region quit smoking and described an abolition of the urge to smoke (42). Animal models have corroborated these effects of insula damage on drug self-administration, with lesions centered on posterior, granular insula (43,44). Therapeutic strategies to reduce insula responsivity, such as mindfulness-or meditationbased techniques (45,46) or GABAergic medications (47), may usefully augment cognitive therapy for psychological distortions in the treatment of problem gambling.…”

Hippocampal and Insular Response to Smoking-Related Environments: Neuroimaging Evidence for Drug-Context Effects in Nicotine Dependence

“…The INS has been proposed as a critical substrate of tobacco use: smokers with insula damage exhibit increased likelihood of quitting smoking Naqvi et al, 2007); selfreported craving (Kuhn and Gallinat, 2011;Tang et al, 2012) and cessation outcomes (Janes et al, 2010) are correlated with insula reactivity to proximal smoking cues; and inactivation of insula decreases proximal cue-provoked nicotine seeking in rodents (Forget et al, 2010;Pushparaj et al, 2013). Less is known about the role of the insula in contextual drug effects; however, in a recent study, insula inactivation in rats led to disruption of amphetamine CPP (Contreras et al, 2012).…”