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. Public Health SignificanceThe effect of the glucocorticoid receptor antagonist PT150 on fentanyl self-administration in male and female rats subjected to early-life stress was examined. Males self-administered more than females, but PT150 eliminated this sex difference, with intake decreasing in males and increasing in females. PT150 may be useful to treat opioid use disorder in males, but not in females.

Xylazine co-self-administration suppresses fentanyl consumption during self-administration and induces a unique sex-specific withdrawal syndrome that is not altered by naloxone in rats

“…Preclinically, studies to date have focused solely on fentanyl self-administration (SA) without the addition of xylazine (e.g., Bardo et al, 2022;Fragale et al, 2020;Hammerslag et al, 2020;Malone et al, 2021) and the only paper to our knowledge that has examined xylazine intravenously did so in combination with ketamine for the purpose of prolonged anesthesia (Linsenmeier et al, 2020). Thus, we conducted a series of behavioral and physiological experiments to examine the following goals.…”

Xylazine suppresses fentanyl consumption during self-administration and induces a unique sex-specific withdrawal syndrome that is not altered by naloxone in rats.

“…Preclinically, studies to date have focused solely on fentanyl self-administration (SA) without the addition of xylazine (e.g., Bardo et al, 2023; Fragale et al, 2021; Hammerslag et al, 2020; Malone et al, 2021), and the only article to our knowledge that has examined xylazine intravenously did so in combination with ketamine for the purpose of prolonged anesthesia (Linsenmeier et al, 2020). Thus, we conducted a series of behavioral and physiological experiments to examine the following goals.…”

Blood Biomarkers in Takotsubo Syndrome Point to an Emerging Role for Inflammaging in Endothelial Pathophysiology

“…Generally, stress responses are inhibited by negative feedback mechanisms, whereby glucocorticoids act to diminish drive (brainstem) and promote transsynaptic inhibition via limbic structures (e.g., hippocampus), including the feedback downregulation of GR [ 61 ]. In contrast, elevated GR [ 62 , 63 ] expression has been described as a suitable surrogate marker and to positively correlate with glucocorticoid resistance in chronic stress [ 64 ]. Chronic stress-induced activation of the hypothalamus–pituitary–adrenal axis takes many forms (chronic basal hypersecretion, sensitized stress responses, and even adrenal exhaustion), with manifestation dependent upon factors such as stressor chronicity, intensity, frequency, and modality which involves GR insensitivity and upregulation [ 61 ].…”