LATERAL ORBITOFRONTAL CORTEX ACTIVITY CONTRIBUTION TO COCAINE-SEEKING: A POPULATIONAL RATHER THAN SPECIFIC GABAERGIC OR GLUTAMATERGIC EFFECT

Cocaine addiction induces complex and severe neurobiological changes, including in the orbitofrontal cortex (OFC). The OFC is an important structure involved in processing cues and reward information, motivated behavior, and cognitive flexibility. Additionally, OFC activity plays an important role in cocaine-seeking and relapse. Therefore, our study evaluated the role of lateral OFC (lOFC) activity in cocaine-seeking behavior and the changes in lOFC neuronal activity induced by cocaine self-administration. Male Sprague-Dawley, GAD-iCre, and CaMKII-cre/ERT2 rats were used. Intrajugular vein catheter implantation and stereotaxic surgeries were conducted. The catheter implant allowed for i.v. cocaine self-administration (0.5mg/kg). Stereotaxic surgeries were conducted for adeno-associated virus (AAV) infusion of iDREADDs (or control, chemogenetic experiments) or GCaMP8m-AAV+optical fiber implantion (for fiber photometry recordings, only Sprague-Dawley rats). Chemogenetic manipulation was conducted during the cue-induced reinstatement test. Recordings of lOFC populational activity were conducted during all behavioral sessions. Overall population-level lOFC chemogenetic inhibition resulted in a significant decrease in active lever-presses during the cue-induced reinstatement test. This result confirms the involvement of the lOFC in cocaine-seeking behavior. However, when GABAergic or glutamatergic populations were specifically chemogenetically inhibited, no significant effect was observed. In order to support these findings, we expect to see a significant overall change in the GCaMP8m signals in the lOFC during the cue-induced reinstatement test. Together, our results demonstrate lOFC involvement in cocaine-seeking behavior, suggesting that its role is driven by overall population activity rather than specific GABAergic or glutamatergic activity.