Lindsey R Hammerslag1, Emily D Denehy1, Benjamin Carper2, Tracy L Nolen2, Mark A Prendergast1, Michael T Bardo3. 1. Department of Psychology, University of Kentucky, BBSRB Room 447, Lexington, KY, 40536-0509, USA. 2. Research Triangle Institute, Research Triangle Park, Durham, NC, USA. 3. Department of Psychology, University of Kentucky, BBSRB Room 447, Lexington, KY, 40536-0509, USA. mbardo@uky.edu.
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.
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.
Authors: Mark A Smith; Sarah B Ethridge; Tallia Pearson; Huailin Zhang; Madison M Marcus; Shannon L Ballard; Alexander T Casimir; Kenzie M Potter; Karl T Schmidt; Jessica L Sharp; Andrea M Robinson Journal: Psychopharmacology (Berl) Date: 2021-01-06 Impact factor: 4.530