Objectives/Goals: To define how stress alters dopamine system function in PTSD with comorbid psychosis and determine whether orexin receptor antagonism with suvorexant can normalize dopamine neuron activity by targeting the insular cortex–orbitofrontal cortex (IC–OFC) circuit. Methods/Study Population: We used in vivo electrophysiology to record ventral tegmental area dopamine neuron population activity in rats following restraint stress. Chemogenetic and pharmacological manipulations targeted the IC–OFC pathway to assess its role in stress-induced dopamine dysregulation. Suvorexant, a dual orexin receptor antagonist, was administered systemically or directly into the OFC. Fiber photometry recordings measured IC-evoked glutamatergic transmission within the OFC to determine how suvorexant modulates circuit-specific activity contributing to altered dopamine function. Results/Anticipated Results: Foot shock stress produced robust increases in dopamine neuron population activity. Intra-OFC suvorexant infusion reversed these effects, restoring dopamine system function to baseline levels. Chemogenetic inhibition of the IC–OFC circuit produced a similar normalization, confirming this pathway’s role in stress-induced dopamine dysregulation. Fiber photometry revealed that suvorexant attenuated IC-evoked glutamatergic signaling in the OFC, indicating that orexin receptor antagonism modulates excitatory input within this cortical circuit to restore balanced dopamine activity. Discussion/Significance of Impact: These findings identify the IC–OFC circuit as a key mediator of stress-induced dopamine dysfunction and reveal orexin receptor antagonism as a promising strategy for treating PTSD with comorbid psychosis. Targeting cortical orexin signaling may enable circuit-specific precision therapies.
Yang et al. (Wed,) studied this question.