An orbitofrontal cortex-anterior insular cortex circuit gates compulsive cocaine use.

Area of Science:

• Neuroscience
• Addiction Research
• Behavioral Pharmacology

Background:

• Compulsive drug use, a hallmark of addiction, involves persistent substance use despite negative outcomes.
• The specific neural circuits underlying compulsive drug-seeking behavior remain largely uncharacterized.

Purpose of the Study:

• To investigate the neural mechanisms driving compulsive cocaine use.
• To identify specific brain regions and circuits involved in the transition to addiction.

Main Methods:

• Utilized a footshock-punished cocaine self-administration paradigm in rats to model compulsive drug use.
• Employed chemogenetics to manipulate the activity of anterior insular cortex (aIC) neurons, particularly glutamatergic neurons.
• Examined the functional connectivity of the orbitofrontal cortex (OFC)-aIC circuit.

Main Results:

• Rats exhibiting compulsive cocaine use showed heightened neural activity in the anterior insular cortex (aIC) compared to non-compulsive rats.
• Chemogenetic modulation of aIC neuronal activity bidirectionally altered compulsive cocaine intake.
• An enhanced OFC-aIC circuit was observed in compulsive cocaine users; its suppression reduced compulsive use, while potentiation increased it.

Conclusions:

• Anterior insular cortex (aIC) glutamatergic neurons and the OFC-aIC circuit play a critical role in gating the shift from controlled to compulsive cocaine use.
• These neural substrates represent potential therapeutic targets for treating drug addiction.