Infralimbic deep brain stimulation during abstinence prevents drug- and stress-induced morphine reinstatement

Relapse remains a primary challenge in Opioid Use Disorder (OUD). While Deep Brain Stimulation (DBS) shows promise, its optimal application is unknown. The infralimbic cortex (IL) is an emerging target for modulating addiction-related behaviors. This study investigated whetherIL DBS administered during passive abstinence, independent of extinction training, could prevent reinstatement of drug preference and act directly on the latent addiction memory. Male Wistar rats underwent conditioned place preference (CPP) with morphine (5 mg/kg, s.c.). During an 8-day abstinence period, animals received daily high-frequency (HFS; 130 Hz) or low-frequency (LFS; 10 Hz) DBS to the IL (200 μA, 60 μs pulse width). Subsequently, reinstatement of morphine-seeking was triggered by either a morphine prime (1 mg/kg, s.c.) or acute restraint stress. The results indicated that both HFS and LFS accelerated the decay of morphine preference during abstinence. In reinstatement tests, HFS robustly blocked the reinstatement of side-preference triggered by both stress and a drug prime. In contrast, LFS entirely blocked drug-primed reinstatement but only partially attenuated stress-induced reinstatement, revealing a significant interaction between DBS frequency and the relapse trigger. IL DBS applied during abstinence prevents opioid reinstatement, suggesting a mechanism involving directly weakening the underlying addiction memory rather than solely facilitating new learning. High-frequency stimulation of the IL appears to be an exceptionally robust, broad-spectrum intervention effective against multiple relapse triggers, offering a promising strategy for OUD treatment.