Infralimbic deep brain stimulation: The impact of frequency and timing on extinction and reinstatement of morphine-seeking behaviors in male rats

Opioid use disorder poses a substantial public health burden. While existing treatments have limitations in achieving long-term abstinence, deep brain stimulation (DBS) emerges as a promising alternative for patients with treatment-refractory addiction. The infralimbic (IL) region has been increasingly recognized by recent studies as a critical brain area involved in addiction, making it a potential target for novel treatments. This study investigates the efficacy of high- and low-frequency DBS within the IL in modulating extinction and reinstatement of morphine-induced conditioned place preference (CPP). After the morphine CPP was established (5 mg/kg; sc), 30-min HFS or LFS session (130 or 10 Hz, 200 μA, 60 μs, respectively) was applied in the IL during two experimental paradigms: daily sessions during the extinction period or a single session prior to the reinstatement test. Following extinction, drug-seeking behavior was reinstated by a morphine priming dose (1 mg/kg; sc). The results indicated that both HFS and LFS during extinction days significantly shortened the extinction duration and prevented the reinstatement of drug-seeking behavior. Furthermore, a single session of DBS prior to priming-dose administration showed that HFS significantly inhibited the reoccurrence of morphine-seeking behavior, while LFS failed to prevent the morphine-primed reinstatement. The results also demonstrated that receiving HFS during the extinction period is more effective in reducing the reinstatement of morphine-seeking behavior compared to that when used in a single session. In conclusion, this research indicates that DBS of the IL can influence addiction-related behaviors across a spectrum of frequencies. Additionally, the therapeutic effectiveness of DBS may vary depending on the timing of its application.