High-Frequency Deep Brain Stimulation of the Substantia Nigra Pars Reticulata Facilitates Extinction and Prevents Reinstatement of Methamphetamine-Induced Conditioned Place Preference.

Libo Zhang,Zengbo Ding,Wenjun Chen,Yisen Liang,Guipeng Zhang,Yun Chen,Shiqiu Meng,Jie Shi,Yu Shi,Enze Huang,Yanxue Xue

doi:10.3389/fphar.2021.705813

Abstract

Persistent and stable drug memories lead to a high rate of relapse among addicts. A number of studies have found that intervention in addiction-related memories can effectively prevent relapse. Deep brain stimulation (DBS) exhibits distinct therapeutic effects and advantages in the treatment of neurological and psychiatric disorders. In addition, recent studies have also found that the substantia nigra pars reticulata (SNr) could serve as a promising target in the treatment of addiction. Therefore, the present study aimed to investigate the effect of DBS of the SNr on the reinstatement of drug-seeking behaviors. Electrodes were bilaterally implanted into the SNr of rats before training of methamphetamine-induced conditioned place preference (CPP). High-frequency (HF) or low-frequency (LF) DBS was then applied to the SNr during the drug-free extinction sessions. We found that HF DBS, during the extinction sessions, facilitated extinction of methamphetamine-induced CPP and prevented drug-primed reinstatement, while LF DBS impaired the extinction. Both HF and LF DBS did not affect locomotor activity or induce anxiety-like behaviors of rats. Finally, HF DBS had no effect on the formation of methamphetamine-induced CPP. In conclusion, our results suggest that HF DBS of the SNr could promote extinction and prevent reinstatement of methamphetamine-induced CPP, and the SNr may serve as a potential therapeutic target in the treatment of drug addiction.

Highlights

Persistent and stable drug memories are considered a major contributor to the intense craving and relapse in drug addiction, which are difficult to eliminate (Hyman and Malenka, 2001; Kauer and Malenka, 2007)
After the rats acquired a preference for methamphetamine, Deep brain stimulation (DBS) was delivered to the substantia nigra pars reticulata (SNr) for 60 min before each extinction test, and at the end of extinction, an injection of methamphetamine was given to evaluate the reinstatement of drug-seeking behavior (Figures 1A,B)
Sham or HF DBS was delivered to the SNr during the drug-free extinction phase, and a two-way repeated measures ANOVA showed overall significant differences in the conditioned place preference (CPP) scores across DBS (F(1, 14) 5.122, p < 0.05) and extinction sessions (F(3.112, 43.57) 3.089, p < 0.05) but not DBS × extinction session interactions (F(5, 70) 0.4994, p 0.7756), which suggests that HF DBS of the SNr facilitated the extinction of methamphetamine-seeking behavior

Summary

Introduction

Persistent and stable drug memories are considered a major contributor to the intense craving and relapse in drug addiction, which are difficult to eliminate (Hyman and Malenka, 2001; Kauer and Malenka, 2007). DBS of SNr Prevents Relapse among addicts (Conklin and Tiffany, 2002; Milton and Everitt, 2012b; Chen et al, 2019b). It has been found that extinction combined with other interventions, such as the retrieval–extinction procedure, can facilitate elimination of drug memories and prevent relapse (He et al, 2011; Xue et al, 2012; Xue et al, 2014; Luo et al, 2015; Liu et al, 2019), which provides a new avenue for the treatment of addiction (Milton and Everitt, 2012a). Preclinical and clinical studies have indicated that DBS may be effective in the treatment of cocaine (Creed et al, 2015), morphine (Martinez-Rivera et al, 2016), and heroin (Chen et al, 2019a) addiction. Proper targets and parameters of DBS in the treatment of addiction are yet to be identified (Wang et al, 2018)

Methods

Results

Conclusion