Bidirectional Modulation of Extinction of Drug Seeking by Deep Brain Stimulation of the Ventral Striatum

Abstract

Background: Recent research in humans and rodents has explored the use of deep brain stimulation (DBS) of the ventral capsule/ventral striatum (VS) as a possible treatment for drug addiction. However, the optimum electrode placement and optimum DBS parameters have not been thoroughly studied. Here we varied stimulation sites and frequencies to determine whether DBS of the VS could facilitate the extinction of morphine-induced conditioned place preference in rats.

Methods: Rats were implanted with DBS electrodes in the dorsal or ventral subregions of the VS and trained to the morphine conditioned place preference. Subsequently, rats received extinction sessions over 9 days, combined with 60 min of either high- (130 Hz) or low- (20 Hz) frequency DBS. To study circuit-wide activations after DBS of the VS, c-fos immunohistochemistry was performed in regions involved in the extinction of drug-seeking behaviors.

Results: High-frequency DBS of the dorsal-VS impaired both extinction training and extinction memory, whereas high-frequency DBS of the ventral-VS had no effect. In contrast, low-frequency DBS of the dorsal-VS strengthened extinction memory when tested 2 or 9 days after the cessation of stimulation. Both DBS frequencies increased c-fos expression in the infralimbic prefrontal cortex, but only low-frequency DBS increased c-fos expression in the basal amygdala and the medial portion of the central amygdala.

Conclusions: Our results suggest that low-frequency (rather than high-frequency) DBS of the dorsal-VS strengthens extinction memory and may be a potential adjunct for extinction-based therapies for treatment-refractory opioid addiction.

Keywords: Amygdala; CPP; DBS; Extinction; Morphine; Ventral striatum.

Figure 1. High frequency DBS of dorsal-VS impairs extinction of morphine-CPP

(A) Diagram showing the CPP-DBS protocol. (B) Representative coronal section of DBS electrode placement in dorsal and ventral-VS (dorsal and ventral to the anterior commissure). (C) High frequency DBS of the dorsal-VS impaired the extinction of morphine-induced CPP, whereas high frequency DBS of the ventral-VS had no effect. (D) There was no effect of DBS on exploratory behavior/locomotion (side changes/transitions) during the CPP-DBS protocol. Sham: n= 23; Dorsal-VS: n= 11; Ventral-VS: n= 9. Data shown as mean and SEM. *p<0.05; **p<0.01.

Figure 2. Low frequency DBS of the dorsal-VS strengthens memory for extinction of morphine-induced CPP

(A) Diagram showing the CPP-DBS protocol. (B) Representative coronal section of DBS electrode placement in the dorsal-VS (dorsal to the anterior commissure). (C) Low frequency DBS of the dorsal-VS reduced the time spent in the drug-paired side during the extinction test (DBS off phase). This effect persisted nine days after stimulation. (D) There was no effect of DBS on exploratory behavior/locomotion (side changes/transitions) during the CPP-DBS protocol. Sham: n= 15; DBS: n= 14. For 1 week test: Sham: n= 7; DBS: n= 7. Data shown as mean and SEM. *p<0.05; **p<0.01.

Figure 3. The effects of high- and low-frequency DBS on c-fos expression in prefrontal, striatal, and amygdala regions

(A) Diagram showing a representative coronal section of DBS electrode placements in the dorsal-VS, for both high-frequency (HF) and low-frequency (LF) groups. (B–C) Both high and low frequency DBS increased c-fos immunoreactivity in IL, whereas neither affected NAc subregions. (D) Only low frequency DBS increased c-fos labeling in the amygdala (BA and CeM). Abbreviations: PL= prelimbic cortex; IL= infralimbic cortex; core= nucleus accumbens core; shell= nucleus accumbens shell; BA= basal nucleus of the amygdala; CeL= lateral portion of the central nucleus of the amygdala; CeM= medial portion of the central nucleus of the amygdala. Sham: n= 6; high frequency DBS: n= 4; low frequency DBS: n= 5. Data represented as mean SEM. *p<0.05; **p<0.01.