Chronic delivery of buprenorphine during abstinence decreases incubation of heroin seeking and neuronal activation in medial prefrontal cortex and striatum in male and female rats

Jennifer M Bossert; Kiera E Caldwell; Hannah Bonbrest; Rohan Patil; Mona S Pishgar; Rajtarun Madangopal; Huiling Wang; Yavin Shaham

doi:10.1007/s00213-025-06971-z

Chronic delivery of buprenorphine during abstinence decreases incubation of heroin seeking and neuronal activation in medial prefrontal cortex and striatum in male and female rats

Psychopharmacology (Berl). 2025 Dec 9. doi: 10.1007/s00213-025-06971-z. Online ahead of print.

Authors

Jennifer M Bossert¹, Kiera E Caldwell², Hannah Bonbrest², Rohan Patil², Mona S Pishgar², Rajtarun Madangopal², Huiling Wang², Yavin Shaham³

Affiliations

¹ Behavioral Neuroscience Branch , IRP/NIDA/NIH, Baltimore, MD, USA. jennifer.bossert@nih.gov.
² Behavioral Neuroscience Branch , IRP/NIDA/NIH, Baltimore, MD, USA.
³ Behavioral Neuroscience Branch , IRP/NIDA/NIH, Baltimore, MD, USA. yavin.shaham@nih.gov.

PMID: 41364217
DOI: 10.1007/s00213-025-06971-z

Abstract

Rationale and objective: Buprenorphine is an FDA-approved medication for opioid addiction, but the brain regions underlying its therapeutic effects remain unknown. We previously found that chronic buprenorphine treatment decreases several relapse-related behaviors in rats. Here, we tested whether chronic buprenorphine decreases the time-dependent increase (incubation) in heroin seeking during abstinence. We also used the activity marker Fos to test whether buprenorphine's inhibition of incubation of heroin seeking is associated with decreased activation of cortical and striatal regions.

Methods: We trained Oprm1-Cre rats and their wild-type littermates to self-administer heroin for 12 days (6 h/day). On abstinence Day 1, we tested for heroin seeking under extinction conditions. On Day 14, we implanted osmotic minipumps containing saline or buprenorphine (6 mg/kg/day). On abstinence Days 21-22, we tested the rats (or not tested, baseline condition) for incubation of heroin seeking, after which brains were collected for Fos immunohistochemistry.

Results: Oprm1-Cre rats did not differ from wild-type littermates in heroin self-administration or 'non-incubated' heroin seeking on abstinence Day 1. In both genotypes, chronic buprenorphine decreased incubated heroin seeking on Days 21-22. Buprenorphine also decreased incubation-related neuronal activation in several cortical areas (cingulate cortex 1 and dorsal peduncular, but not prelimbic, infralimbic, or orbitofrontal cortex) and striatal areas (dorsolateral and dorsomedial striosomes and nucleus accumbens core, but not shell).

Conclusions: Chronic buprenorphine decreased incubation of heroin seeking, supporting the predictive validity of the rat model. This effect was associated with decreased neuronal activity in specific subregions of the medial prefrontal cortex and striatum.

Keywords: Buprenorphine; Context-induced reinstatement; Drug self-administration; Heroin; Incubation of drug craving.