MODULATION OF VENTRAL TEGMENTAL AREA ACTIVITY BY THE ANTERIOR INSULAR CORTEX IN THE CONTEXT OF COCAINE ADDICTION

Cocaine addiction is a chronic relapsing disorder with high relapse rates, even after prolonged abstinence, reflecting persistent adaptations in addiction-related brain circuits. In 2007, lesions of the insular cortex (IC) were shown to reduce craving and drug consumption in individuals with nicotine addiction. Since then, numerous clinical and preclinical studies have highlighted the IC, particularly its anterior subdivision (aIC), in addiction and relapse. Additionally, the aIC is connected to brain regions involved in the hypodopaminergic state observed in the ventral tegmental area (VTA) following longterm abstinence. This study aims to determine how the aIC influences VTA dopaminergic neurons during abstinence, including whether this modulation occurs through direct or indirect pathways and contributes to relapse-related behaviors. Male Sprague–Dawley rats self-administered cocaine for 10 days or remained drug-naive. After 30 days of abstinence, in vivo extracellular recordings were performed from VTA dopaminergic neurons. Tonic (population activity, firing rate) and phasic (burst firing) activity were assessed following pharmacological or electrical manipulation of the aIC, basolateral amygdala (BLA) and ventral pallidum (VP). In cocaine-exposed rats, aIC inhibition via low frequency stimulation was combined with cue-induced cocaine seeking tests. After abstinence, cocaine-exposed rats showed reduced VTA dopaminergic population activity without changes in firing rate or burst firing. In naive rats, aIC activation decreased VTA population activity via the BLA-VP pathway. In cocaine-abstinent rats, aIC inactivation reversed the hypodopaminergic state and reduced cue-induced cocaine seeking. These findings identify the aIC-BLA-VP-VTA circuit as a critical regulator of dopaminergic dysfunction and relapse vulnerability during cocaine abstinence.