Role of orbitofrontal cortex in relapse to fentanyl seeking after food-choice induced voluntary abstinence

There are few preclinical studies of fentanyl relapse, and these studies have used experimenter-imposed (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 rewards. We recently developed a rat model of relapse after food choice-induced voluntary abstinence. Here we used the model to study the role of orbitofrontal cortex (OFC), previously implicated in heroin relapse after forced abstinence, in relapse to fentanyl seeking after voluntary abstinence. We trained male and female rats to self-administer palatable food pellets for 6 days (6-h/day) and fentanyl (2.5 microgram/kg/infusion, i.v.) for 12 days (6-h/day). We assessed relapse to fentanyl seeking after 14 voluntary abstinence days, achieved through a discrete choice procedure between fentanyl and palatable food (20 trials/day). In both sexes, relapse was associated with increased expression of the activity marker Fos in lateral and ventral orbitofrontal cortex (OFC). Reversible inactivation of either subregion with GABA-A and GABA-B receptor agonists muscimol and baclofen (50+50 ng/side) decreased relapse to fentanyl seeking. We next 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 neurons projecting to OFC, but not OFC-projecting basolateral amygdala or thalamic neurons. Results demonstrate a role of OFC in relapse to fentanyl seeking after voluntary abstinence and suggest a potential role of the projection from piriform cortex to OFC in this relapse.