CORTICO-SUBTHALAMIC PATHWAYS MEDIATE SOCIAL MODULATION OF COCAINE SELF-ADMINISTRATION IN RATS

Cocaine addiction is an increasing public health issue with yet no effective pharmacological treatment. Social context can significantly modulate drug intake. Notably, the presence of a peer can reduce cocaine use in rats via a neurobiological substrate that involves the subthalamic nucleus (STN) but remains to be identified. We therefore investigated how cortico-subthalamic projections (the so-called “hyperdirect pathways”) from the prelimbic cortex (PL) and anterior insula (AI)—both critical hubs in addiction—mediate this social regulation across varying social contexts. Male rats underwent optogenetic inhibition of either PL-STN or AI-STN projections during cocaine self-administration (250 μg/90 μl; FR1) in various social contexts: alone or in presence of an unfamiliar, cocaine naive peer, male or female. The presence of either a male or a female peer significantly reduced cocaine intake. The reduction was less pronounced when the peer was a female than a male. Optogenetic inhibition of the PL-STN pathway reduced cocaine consumption when the animals were alone, while inhibition of the AI-STN pathway only diminished the drug intake when combined with the presence of a peer. These findings demonstrate that PL-STN and AI-STN circuits differentially integrate social signals to regulate cocaine-seeking behavior. These results identify cortico-STN networks as potential therapeutic targets for modulating the environmental and social determinants of addiction.