Prelimbic-to-Naccore mechanisms behind maladaptive cocaine seeking – COCADAPT

Cocaine use is increasing in France and Europe. Approximately 15-20% of cocaine users become addicted, and there is currently no approved pharmacological treatment for this addiction.
A critical clinical and societal challenge of cocaine addiction is maladaptive drug-seeking, i.e. seeking drugs when it is not beneficial and may even be harmful to the user. Maladaptive cocaine seeking is proposed to result from a diminished ability to exert control over a heightened response to drug-related incentives. However, the specific interplay between these two processes in contributing to addiction development and the underlying psychobiological mechanisms remain poorly understood. Based on a preclinical model with translational value, our objective is to compare these interactions and mechanisms in individuals identified as being at risk (vulnerable) or not (resilient) for cocaine addiction.
The neurons in the prelimbic cortex (PL) projecting to the nucleus accumbens core (Naccore) are strong candidates for integrating contextual information (both internal and external) and adaptively regulating responses to drug-related incentives dependent on dopamine within the Naccore. Our study aims to establish the links between the activity of PL-Naccore neurons and dopamine levels in the Naccore while individuals are prompted to seek drugs in a context where such seeking is maladaptive. By focusing on the study of individual vulnerability differences and combining drug self-administration with real-time fiber photometry recordings and optogenetics, our project will provide insights into the underlying mechanisms of the inability to inhibit cocaine seeking in an adaptive manner. This should contribute to the understanding and enhancement of promising behavioral therapies based on the restoration of these impaired processes.