An orbitofrontal cortex–anterior insular cortex circuit gates compulsive cocaine use

Abstract

Compulsive drug use, a cardinal symptom of drug addiction, is characterized by persistent substance use despite adverse consequences. However, little is known about the neural circuit mechanisms behind this behavior. Using a footshock-punished cocaine self-administration procedure, we found individual variability of rats in the process of drug addiction, and rats with compulsive cocaine use presented increased neural activity of the anterior insular cortex (aIC) compared with noncompulsive rats. Chemogenetic manipulating activity of aIC neurons, especially aIC glutamatergic neurons, bidirectionally regulated compulsive cocaine intake. Furthermore, the aIC received inputs from the orbitofrontal cortex (OFC), and the OFC-aIC circuit was enhanced in rats with compulsive cocaine use. Suppression of the OFC-aIC circuit switched rats from punishment resistance to sensitivity, while potentiation of this circuit increased compulsive cocaine use. In conclusion, our results found that aIC glutamatergic neurons and the OFC-aIC circuit gated the shift from controlled to compulsive cocaine use, which could serve as potential therapeutic targets for drug addiction.

High frequency deep brain stimulation of the dorsal raphe nucleus prevents methamphetamine priming-induced reinstatement of drug seeking in rats

“…Meanwhile, we also observed that high-frequency DBS of the DRN led to activation in both the OFC and VTA. The OFC plays a fundamental role in motivated behavior, and deficits in its function elicit not only impulsive but also compulsive behaviors, which may underlie the mechanism of compulsive drug seeking and relapse [ 37 , 38 ]. In line with our findings, high-frequency DBS of the OFC has also been shown to reduce the methamphetamine-induced reinstatement of seeking behaviors [ 39 ].…”

The gut microbiome modulates the susceptibility to traumatic stress in a sex‐dependent manner

“…Building upon the cluster analysis method employed in previous article (Chen, Wang, et al., 2022; Li et al., 2021), we adjusted the behavioral indicators and categorized the animals into stress‐susceptibility and stress‐resilience after SPS. The cluster analysis was conducted utilizing Python.…”

“…Building upon the cluster analysis method employed in previous article (Chen, Wang, et al, 2022;Li et al, 2021) ("t-sne" of "sklearn.manifold;" dimension number, 3) was applied to the five normalized variables. The three dimensions were clustered by "Agglomerative Clustering" of "sklearn.cluster."…”

Linking drug and food addiction: an overview of the shared neural circuits and behavioral phenotype

“…Imaging studies have reported differential activation of the insula during craving, possibly reflecting interoceptive cues and the activation of corticotropin-releasing factor ( Mar et al, 2011 ). The OFC-anterior insular cortex pathway is also involved in cocaine addiction ( Chen et al, 2022 ) and, interestingly, using a continuous versus intermittent cocaine self-administration paradigm, it has been found that the latter was able to induce greater cocaine-taking behavior during withdrawal ( Luo et al, 2021 ). The same effect, mediated by an intermittent (but not continuous) self-administration paradigm, has been reported for HPF ( Spierling et al, 2020 ).…”