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Role of projections between piriform cortex and orbitofrontal cortex in relapse to fentanyl seeking after palatable food choice-induced voluntary abstinence

Reiner, DJ;Lofaro, OM;Applebey, SV;Korah, H;Venniro, M;Cifani, C;Bossert, JM;Shaham, Y;

We recently developed a rat model of relapse to drug seeking after food choice-induced voluntary abstinence. Here we used this model to study the role of orbitofrontal cortex (OFC) and its afferent projections in relapse to fentanyl seeking. We trained male and female rats to self-administer palatable food pellets for 6 days (6-h/day) and intravenous fentanyl (2.5 g/kg/infusion) for 12 days (6-h/day). We assessed relapse to fentanyl seeking after 13-14 voluntary abstinence days, achieved through a discrete choice procedure between fentanyl infusions and palatable food (20 trials/day). In both sexes, relapse after food choice-induced abstinence was associated with increased expression of the activity marker Fos in OFC. Pharmacological inactivation with muscimol+baclofen (50+50 ng/side) of OFC decreased relapse to fentanyl seeking. We then determined projection-specific activation of OFC afferents during the relapse test by using Fos plus the retrograde tracer cholera toxin B (injected into OFC). Relapse to fentanyl seeking was associated with increased Fos expression in piriform cortex (Pir) neurons projecting to OFC, but not in projections from basolateral amygdala and thalamus. Pharmacological inactivation of Pir with muscimol+baclofen decreased relapse to fentanyl seeking after voluntary abstinence. Next, we used an anatomical disconnection procedure to determine whether projections between Pir and OFC are critical for relapse to fentanyl seeking. Unilateral muscimol+baclofen injections into Pir in one hemisphere plus unilateral muscimol+baclofen injections into OFC in the contralateral but not ipsilateral hemisphere decreased relapse. Our results identify Pir-OFC projections as a new motivation-related pathway critical to relapse to opioid seeking after voluntary abstinence.SIGNIFICANCE STATEMENTThere are few preclinical studies of fentanyl relapse and these studies have used experimenter-imposed extinction or forced abstinence procedures. In humans, however, abstinence is often voluntary, with drug available in the drug environment but forgone in favor of non-drug alternative reinforcers. We recently developed a rat model of drug relapse after palatable food choice-induced voluntary abstinence. Here we used classical pharmacology, immunohistochemistry, and retrograde tracing to demonstrate a critical role of the piriform and orbitofrontal cortices in relapse to opioid seeking after voluntary abstinence. Copyright 2020 the authors.