Continuous High Frequency Deep Brain Stimulation of the Rat Anterior Insula Attenuates the Relapse Post Withdrawal and Strengthens the Extinction of Morphine Seeking

Abstract

Deep brain stimulation (DBS) modulates the neuronal activity in specific brain circuits and has been recently considered as a promising intervention for refractory addiction. The insula cortex is the hub of interoception and is known to be involved in different aspects of substance use disorder. In the present study, we investigate the effects of continuous high frequency DBS in the anterior insula (AI) on drug-seeking behaviors and examined the molecular mechanisms of DBS action in morphine-addicted rats. Sprague-Dawley rats were trained to the morphine-conditioned place preference (CPP, day 1–8) followed by bilaterally implanted with DBS electrodes in the AI (Day 10) and recovery (Day 10–15). Continuous high-frequency (HF) -DBS (130 Hz, 150 μA, 90 μs) was applied during withdrawal (Day 16–30) or extinction sessions. CPP tests were conducted on days 16, 30, 40 during withdrawal session and several rats were used for proteomic analysis on day 30. Following the complete extinction, morphine-CPP was reinstated by a priming dose of morphine infusion (2 mg/kg). The open field and novel objective recognition tests were also performed to evaluate the DBS side effect on the locomotion and recognition memory. Continuous HF-DBS in the AI attenuated the expression of morphine-CPP post-withdrawal (Day 30), but morphine addictive behavior relapsed 10 days after the cessation of DBS (Day 40). Continuous HF-DBS reduced the period to full extinction of morphine-CPP and blocked morphine priming-induced recurrence of morphine addiction. HF-DBS in the AI had no obvious effect on the locomotor activity and novel objective recognition and did not cause anxiety-like behavior. In addition, our proteomic analysis identified eight morphine-regulated proteins in the AI and their expression levels were reversely changed by HF-DBS. Continuous HF-DBS in the bilateral anterior insula prevents the relapse of morphine place preference after withdrawal, facilitates its extinction, blocks the reinstatement induced by morphine priming and reverses the expression of morphine-regulated proteins. Our findings suggest that manipulation of insular activity by DBS could be a potential intervention to treat substance use disorder, although future research is warranted.

Continuous high-frequency deep brain stimulation of the anterior insula modulates autism-like behavior in a valproic acid-induced rat model

“…We have observed that the expression levels of the Npas4, Arc, and c-Fos genes in the AI of the VPA-exposed animals were considerably elevated as opposed to that of rats in the Saline group, which may be related to abnormal responses to neuronal activity in neural circuits [ 31 , 37 ]. Interestingly, long-term HF-DBS increased the expression of the IEGs in the AI of the saline-DBS group, and conversely reduced the expression of IEGs in the VPA-DBS group, suggesting that our DBS protocol dynamically modulated the AI neuronal activity, and this is consistent with previous studies [ 36 , 38 , 39 ].…”

“…In this research, we first implanted electrodes into rats that had been subjected to valproic acid treatment to cause autism, and then we stimulated the animals thereafter. In addition, we used a novel design informed by prior research with an implantable stimulation generator, which allowed the test subjects to move and eat unrestrictedly and provide long-term chronic stimulation (effective voltage output for three months) [ 36 ]. We have observed that the expression levels of the Npas4, Arc, and c-Fos genes in the AI of the VPA-exposed animals were considerably elevated as opposed to that of rats in the Saline group, which may be related to abnormal responses to neuronal activity in neural circuits [ 31 , 37 ].…”

Role of deep brain stimulation (DBS) in addiction disorders

“…show that the continuous HF-DBS applied to the bilateral anterior insula prevents the relapse of morphine place preference following withdrawal, facilitates its extinction, blocks reinstatement triggered by morphine priming, and reverses the expression of morphine-regulated proteins. [ 10 ] These findings, combined with previous research, suggest that modulating insular activity through pharmacological or other methods, such as DBS, holds promise as a potential treatment for SUD.…”

On the Role of Insula in Drug Addiction

“…Further detection of insular lobe brain slices showed that high-frequency electrical stimulation can inactivate insular lobe neurons. Continuous DBS in the anterior insula can inhibit the recurrence of morphine CPP in rats and promote its regression (65). In a study, in which DBS targeted regions ranging from the lateral orbitofrontal cortex to the dorsal portion of the agranular insula, showed that high-frequency DBS blocks the acquisition of morphine preference, promotes extinction of morphine preference, and prevents drug-induced morphine igniting (66).…”