Examining the Role of the Insular Cortex in Addiction-relevant Behaviours

INTRODUCTION: Recently recognized as a critical brain region underlying the neurocircuitry of addiction, the body of evidence supporting the role of the insular cortex across multiple aspects of addiction is growing rapidly. Understanding the complex role of the insular cortex is crucial to moving forward with the development of therapeutics targeting this brain region for substance-related and addictive disorders. OBJECTIVES: The current series of experiments were conducted to investigate the effects of modulating activity in two insular subregions, through the use of multiple modalities (chemical lesions, pharmacological inactivation or electrical stimulation), on behaviours relevant to addictive disorders, including drug self-administration, reinstatement, and decision-making. METHODS: In the first series of experiments, we investigated the effects of chemical lesions or transient pharmacological inactivation of two distinct subregions of the insular cortex, the rostral agranular (RAIC) vs. caudal granular (CGIC), on the acquisition or performance of choice behaviour in the Rat Gambling Task (rGT). In the next series of experiments, we examined the effects of pharmacological inactivation of the RAIC on nicotine self-administration under a fixed ratio-5 (FR-5) schedule of reinforcement and the reinstatement of nicotine-seeking induced by nicotine-associated cues. Finally, we examined the effects of electrical modulation of the insular region on nicotine self-administration under both FR-5 and progressive ratio schedules of reinforcement and the reinstatement of nicotine-seeking by cues and nicotine priming injections. RESULTS: Lesions of the RAIC, but not CGIC, resulted in higher preference for options which produced lower reward amounts with higher reward consistency while inactivation of the RAIC, but not CGIC, shifted previously acquired preferences towards those same low reward/high consistency options. Inactivation of the RAIC attenuated nicotine self-administration and cue-induced reinstatement. Finally, electrical modulation functionally inactivated the insular region, resulting in attenuated nicotine self-administration, under FR-5 and progressive ratios, and of cue- and priming-induced reinstatement. CONCLUSIONS: This work demonstrates involvement of the RAIC, but not CGIC, in cognitive aspects of addictive disorders, such as gambling-relevant behaviours. Yet both regions were demonstrated to be implicated in substance-based addictive disorders. Thus, therapeutics using electrical modulation to target the CGIC may be preferable for substance dependence, with limited cognitive side effects.Ph.D