Role of submedius thalamus and its interaction with orbitofrontal cortex in incubation of oxycodone craving

A major obstacle in oxycodone addiction treatment is relapse during abstinence. In rats, oxycodone seeking intensifies during abstinence, and orbitofrontal cortex (OFC) is critical for this incubation. Here we studied the role of submedius thalamus (Sub) and its reciprocal connections with OFC in this incubation in male rats. First, using the pharmacological inactivation approach, we examined the causal role of Sub in incubation of oxycodone craving. Next, combining fluorescence-conjugated cholera toxin subunit b (a retrograde tracer) with Fos (a neuronal activity marker), we assessed whether the activation of Sub and OFC connections was associated with incubated oxycodone seeking on abstinence day 15. Using an anatomical disconnection procedure, we then examined the causal role of interactions between Sub and OFC in incubated oxycodone seeking. We also tested the effect of unilateral Sub inactivation on incubated oxycodone seeking, and contralateral disconnection of Sub and OFC on non-incubated oxycodone seeking on abstinence day 1. We found that bilateral Sub inactivation decreased oxycodone seeking on abstinence day 15 but not on day 1, and incubated oxycodone seeking was associated with activation of both Sub→OFC and OFC→Sub projections. Further, both contralateral and ipsilateral disconnection of Sub and OFC decreased incubated oxycodone seeking. Unilateral Sub inactivation had no effect on the total responding during oxycodone seeking but impacted within-session responses. Lastly, contralateral disconnection of Sub and OFC had no effect on non-incubated oxycodone seeking. Together, these results demonstrated a novel role of Sub and its interactions with OFC in incubation of oxycodone craving.