Distinct suppressing effects of deep brain stimulation in the orbitofrontal cortex on the development, extinction, and reinstatement of methamphetamine-seeking behaviors

Aims: The orbitofrontal cortex (OFC) is implicated in compulsive drug-seeking and relapse, the characteristics that result in addiction treatment failure. Structural and functional impairments within the OFC have been detected in many substance use disorders (SUDs). Deep brain stimulation (DBS) is proposed as a promising therapeutic option in treating SUDs. Therefore, the present study aimed to investigate the potential efficacy of DBS application on the various stages of the methamphetamine-conditioned place preference (CPP) paradigm in rats.Main methods: Electrodes were implanted unilaterally in the rat's right OFC. DBS in the form of high-or low-frequency stimulation (HFS: 130 Hz, LFS: 13 Hz) was applied during the 5-day conditioning phase (a daily 30-min session) or extinction period (30-min session, daily, ten days) of methamphetamine-induced CPP in two separate sets of experiments. Following extinction, place preference was reinstated by injecting a priming dose of methamphetamine (0.25 mg/kg).Key findings: The HFS and LFS significantly decreased the methamphetamine place preference when applied over the conditioning period. In the extinction experiment, only HFS could remarkably accelerate the extinction of reward-context associations and even reduce the methamphetamine-induced reinstatement of seeking behaviors. Significance: Conclusively, DBS administration in the OFC demonstrated some positive results, including sup-pressing effects on the development, maintenance, and relapse of methamphetamine-seeking behavior. These findings encourage conducting more preclinical studies to strongly suggest a wide range of DBS applications in cortical areas such as OFC as an efficient treatment modality for psychostimulant use disorder.