The Role of Claustrum in Incubation of Opioid Seeking after Electric Barrier-Induced Voluntary Abstinence in Male and Female Rats.

We previously reported that ventral subiculum (vSub) activity is critical to incubation of oxycodone seeking after abstinence induced by adverse consequences of drug seeking. Here, we studied the role of claustrum, a key vSub input, in this incubation. We trained male and female rats to self-administer oxycodone for 2†weeks and then induced abstinence by exposing them to an electric barrier for 2†weeks. We used retrograde tracing (cholera toxin B subunit) plus the activity marker Fos to identify projections to vSub cactivated during "incubated" relapse (Abstinence Day 15). We then used pharmacological reversible inactivation to determine the causal role of claustrum in incubation and the behavioral and anatomical specificity of this role. We also used an anatomical disconnection procedure to determine the causal role of claustrum-vSub connections in incubation. Finally, we analyzed an existing functional MRI dataset to determine if functional connectivity changes in claustrum-related circuits predict incubation of oxycodone seeking. Claustrum neurons projecting to vSub were activated during relapse tests after electric barrier-induced abstinence. Inactivation of claustrum but not areas dorsolateral to claustrum decreased incubation of oxycodone seeking after electric barrier-induced abstinence; claustrum inactivation had no effect on incubation after food choice-induced abstinence. Both ipsilateral and contralateral inactivation of claustrum-vSub projections decreased incubation after electric barrier-induced abstinence. Functional connectivity changes in claustrum-cortical circuits during electric barrier-induced abstinence predicted incubated oxycodone relapse. Our study identified a novel role of claustrum in relapse to opioid drugs after abstinence induced by adverse consequences of drug seeking.