Effect of the glucocorticoid receptor antagonist PT150 on acquisition and escalation of fentanyl self-administration following early-life stress

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. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Figure 1.. Schematic of Timeline.

Timeline depicting sequence of social isolation and acute stress treatments, followed by PT150 treatment and assessment of fentanyl self-administration.

Figure 2.. Corticosterone Levels.

Mean (±SEM) plasma corticosterone levels for males (left panel) and females (right panel) measured prior to acute stress, immediately after acute stress and 1 hr after termination of acute stress.

Figure 3.. Acquisition of Fentanyl Self-Administration During 1-hr Sessions.

Mean (±SEM) number of fentanyl infusions earned in 1-hr self-administration sessions for social-housed males and females given either PT150 or placebo (panel a) and isolate-housed males and females given either PT150 or placebo (panel b). For clarity, data are collapsed across the acute stress treatment, as that factor yielded no significant effect in the statistical model.

Figure 4.. Escalation of Fentanyl Self-Administration During 6-hr Sessions.

Mean (±SEM) number of infusions earned in 6-hr self-administration sessions for social-housed males and females given either PT150 or placebo (panel a) and isolate-housed males and females given either PT150 or placebo (panel b). For clarity, data are collapsed across the acute stress treatment, as that factor yielded no significant effect in the statistical model.