Role of Projections between Piriform Cortex and Orbitofrontal Cortex in Relapse to Fentanyl Seeking after Palatable Food Choice-Induced Voluntary Abstinence

Study Coauthors Olivia Lofaro and Sarah Applebey

Featured Paper of the Month – August 2020.

Fentanyl is a major contributor to the opioid overdose crisis, but there are few preclinical studies of fentanyl relapse. 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 nondrug 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 fentanyl seeking after voluntary abstinence. Our results demonstrate a new role of the olfaction-related piriform cortex in opioid relapse.

Publication Information

Reiner, David J; Lofaro, Olivia M; Applebey, Sarah V; Korah, Hannah; Venniro, Marco; Cifani, Carlo; Bossert, Jennifer M; Shaham, Yavin

Role of Projections between Piriform Cortex and Orbitofrontal Cortex in Relapse to Fentanyl Seeking after Palatable Food Choice-Induced Voluntary Abstinence Journal Article

In: Journal of Neuroscience, vol. 40, no. 12, pp. 2485–2497, 2020, ISSN: 0270-6474.

Abstract | Links

@article{Reiner2485,

title = {Role of Projections between Piriform Cortex and Orbitofrontal Cortex in Relapse to Fentanyl Seeking after Palatable Food Choice-Induced Voluntary Abstinence},

author = {David J Reiner and Olivia M Lofaro and Sarah V Applebey and Hannah Korah and Marco Venniro and Carlo Cifani and Jennifer M Bossert and Yavin Shaham},

url = {https://pubmed.ncbi.nlm.nih.gov/32051327/},

doi = {10.1523/JNEUROSCI.2693-19.2020},

issn = {0270-6474},

year  = {2020},

date = {2020-01-01},

journal = {Journal of Neuroscience},

volume = {40},

number = {12},

pages = {2485--2497},

publisher = {Society for Neuroscience},

abstract = {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 the 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 d (6 h/d) and intravenous fentanyl (2.5 μg/kg/infusion) for 12 d (6 h/d). 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/d). In both sexes, relapse after food choice-induced abstinence was associated with increased expression of the activity marker Fos in the OFC. Pharmacological inactivation of the OFC with muscimol plus baclofen (50 + 50 ng/side) 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 the OFC). Relapse to fentanyl seeking was associated with increased Fos expression in the piriform cortex (Pir) neurons projecting to the OFC, but not in projections from the basolateral amygdala and thalamus. Pharmacological inactivation of the Pir with muscimol plus baclofen decreased relapse to fentanyl seeking after voluntary abstinence. Next, we used an anatomical disconnection procedure to determine whether projections between the Pir and OFC are critical for relapse to fentanyl seeking. Unilateral muscimol plus baclofen injections into the Pir in one hemisphere plus unilateral muscimol plus baclofen injections into the 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 STATEMENT There 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 nondrug 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.},

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pubstate = {published},

tppubtype = {article}

}

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 the 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 d (6 h/d) and intravenous fentanyl (2.5 μg/kg/infusion) for 12 d (6 h/d). 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/d). In both sexes, relapse after food choice-induced abstinence was associated with increased expression of the activity marker Fos in the OFC. Pharmacological inactivation of the OFC with muscimol plus baclofen (50 + 50 ng/side) 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 the OFC). Relapse to fentanyl seeking was associated with increased Fos expression in the piriform cortex (Pir) neurons projecting to the OFC, but not in projections from the basolateral amygdala and thalamus. Pharmacological inactivation of the Pir with muscimol plus baclofen decreased relapse to fentanyl seeking after voluntary abstinence. Next, we used an anatomical disconnection procedure to determine whether projections between the Pir and OFC are critical for relapse to fentanyl seeking. Unilateral muscimol plus baclofen injections into the Pir in one hemisphere plus unilateral muscimol plus baclofen injections into the 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 STATEMENT There 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 nondrug 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.