Abstract
Rationale
Opioid use disorder (OUD) is highly comorbid with stress-related disorders, and stress can serve as a trigger for reinstatement of drug seeking. Glucocorticoid receptor (GR) antagonists such as mifepristone (RU-486) may be effective against stress-induced drug seeking. In the current study, PT150 (formerly ORG-34517), a more selective GR antagonist, was tested using two models of stress-induced drug seeking, namely footshock and yohimbine.
Methods
Adult male and female Sprague-Dawley rats were trained to self-administer fentanyl (2.5 μg/kg/infusion, i.v.) in a model of escalation. Rats then received 7 days of abstinence, followed by extinction; PT150 (0, 50 or 100 mg/kg in Nutella®; p.o.) treatment started on the first day of extinction training and continued daily until the end of the study. Following 14 days of extinction, rats were tested for reinstatement following footshock and yohimbine (0, 1, or 2 mg/kg; i.p.), tested in counterbalanced order; PT150 or placebo treatment occurred prior to each extinction and reinstatement session.
Results
Prior to initiation of PT150 treatment, females self-administered greater levels of fentanyl during 1-h sessions compared to males; however, when switched to 6-h sessions, males and females self-administered similar levels of fentanyl and showed a similar escalation of intake over time. PT150 had no effect on extinction of self-administration. While both footshock and yohimbine reinstated fentanyl seeking, only footshock-induced reinstatement was decreased by PT150 (50 and 100 mg/kg). The effect of PT150 on footshock-induced reinstatement was driven primarily by males.
Conclusion
The glucocorticoid antagonist PT150 reduces shock-induced fentanyl seeking, suggesting it may be effective against stress-induced relapse, although the sex difference in response may need further exploration.
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Funding
This work was supported by the Office of the Assistant Secretary of Defense for Health Affairs through the Alcohol and Substance Abuse Research Program under Award No. W81XWH-18-2-0044. The US Army Medical Research Acquisition Activity, 820 Chandler Street, Fort Detrick, MD, 21702-5014, is the awarding and administering acquisition office. In addition, LRH was supported by NIH training grant T32 DA16176 and MTB was supported by NIH grants R21 DA041755 and R01 DA053070.
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In conducting research using animals, the investigators adhered to the laws of the USA and regulations of the Department of Agriculture. All experimental procedures were approved by the Institutional Animal Care and Use Committee at the University of Kentucky and conformed to the National Institutes of Health Guide for the Care and Use of Laboratory Animals.
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MAP and MTB serve as scientific advisors for and have stock options with Pop Test Oncology/Palisades Therapeutics LLC, Cliffside Park, NJ. Any potential royalty stream would be consistent with University of Kentucky policy. A conflict of interest management plan was used to mitigate the risk, with raw data transferred to RTI and all analyses conducted by BC.
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Hammerslag, L.R., Denehy, E.D., Carper, B. et al. Effects of the glucocorticoid receptor antagonist PT150 on stress-induced fentanyl seeking in male and female rats. Psychopharmacology 238, 2439–2447 (2021). https://doi.org/10.1007/s00213-021-05865-0
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DOI: https://doi.org/10.1007/s00213-021-05865-0