Orbitofrontal cortex to dorsal striatum circuit is critical for incubation of oxycodone craving after forced abstinence

Relapse is a major challenge in treating opioid addiction, including oxycodone. During abstinence, oxycodone seeking progressively increases, and we previously demonstrated a causal role of the orbitofrontal cortex (OFC) in this incubation of oxycodone craving after forced abstinence. Here, we explored critical downstream targets of OFC by focusing on dorsal striatum (DS). We first examined dorsal striatal Fos (a neuronal activity marker) expression associated with oxycodone seeking after abstinence. Using a dopamine D1 receptor (D1R) antagonist, we also tested the causal role of DS in incubated oxycodone seeking. Next, we combined fluorescence-conjugated cholera toxin subunit B (CTb-555, a retrograde tracer) with Fos to assess whether the activation of OFC → DS projections was associated with incubated oxycodone seeking. We then used a series of pharmacological procedures to examine the causal role of the interaction between glutamatergic projections from OFC and D1R signaling in DS in incubation of oxycodone craving. We found that dorsal striatal Fos expression in DS exhibited a time-dependent increase in parallel with incubation of oxycodone craving, and DS inactivation decreased incubated oxycodone seeking. Moreover, OFC → DS projections were activated during incubated oxycodone seeking, and anatomical disconnection of OFC → DS projections, but not unilateral inactivation of OFC or DS, decreased incubated oxycodone seeking. Lastly, contralateral disconnection of OFC → DS projections had no effect on oxycodone seeking on abstinence day 1. Together, these results demonstrated a causal role of OFC → DS projections in incubation of oxycodone craving.