Effect of the Glucocorticoid Receptor Antagonist PT150 on Acquisition and Escalation of Fentanyl Self-Administration Following Early-Life Stress

Michael T. Bardo, Cassie M. Chandler, Emily D. Denehy, Benjamin A. Carper, Mark A. Prendergast, Tracy L. Nolen

Research output: Contribution to journalArticlepeer-review

Abstract

There is comorbidity between posttraumatic stress disorder (PTSD) and opioid use disorder (OUD), perhaps because PTSD-like stressful experiences early in life alter the hypothalamic–pituitary-adrenal stress axis to increase the risk for OUD. The present study determined if the glucocorticoid receptor antagonist PT150 reduces the escalation of fentanyl intake in rats exposed to a “two-hit” model of early-life stress (isolation rearing and acute stress). Male and female rats were raised during adolescence in either isolated or social housing and then were given either a single acute stress (restraint and cold-water swim) or control treatment in young adulthood. Rats were then treated daily with PT150 (50 mg/kg, oral) or placebo and were tested for acquisition of fentanyl self-administration in 1-hr sessions, followed by escalation across 6-hr sessions. Regardless of PT150 treatment or sex, acquisition of fentanyl self-administration in 1-hr sessions was greater in isolate-housed rats compared to social-housed rats; the acute stress manipulation did not have an effect on self-administration even though it transiently increased plasma corticosterone levels. During the 6-hr sessions, escalation of fentanyl was observed across all treatment groups; however, there was a significant PT150 Treatment × Sex interaction. While males self-administered more than females overall, PT150 decreased intake in males and increased intake in females, thus negating the sex difference. Although PT150 may serve as an effective treatment for reducing the risk of OUD following early-life stress in males, further work is needed to determine the mechanism underlying the differential effects of PT150 in males and females.

Original languageEnglish
JournalExperimental and Clinical Psychopharmacology
DOIs
StateAccepted/In press - 2022

Bibliographical note

Funding Information:
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. Opinions, interpretations, conclusions, and recommendations are those of the author and are not necessarily endorsed by the Department of Defense. The U.S. Army Medical Research Acquisition Activity, 820 Chandler Street, Fort Detrick MD 21702-5014, USA was the awarding and administering acquisition office. In addition, Cassie M. Chandler was supported by NIH training Grant T32 DA035200 and Michael T. Bardo was supported by NIH Grant R01 DA053070.

Publisher Copyright:
© 2022. American Psychological Association

Keywords

  • Corticosterone
  • Fentanyl
  • Posttraumatic stress disorder (ptsd)
  • Pt150
  • Social isolation

ASJC Scopus subject areas

  • Pharmacology
  • Psychiatry and Mental health
  • Pharmacology (medical)

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