Elsevier

Psychiatry Research

Volume 269, November 2018, Pages 529-535
Psychiatry Research

The anxiolytic-like effects of estazolam on a PTSD animal model

https://doi.org/10.1016/j.psychres.2018.08.118Get rights and content

Highlights

  • PTSD-like behavioral deficits were induced by single prolonged stress.

  • Estazolam produced the anti-PTSD-like effects.

  • Estazolam promoted biosynthesis of allopregnanolone.

  • The anti-PTSD-like effects of estazolam were associated with allopregnanolone.

Abstract

Post-traumatic stress disorder (PTSD) is a serious psychiatric disorder. Estazolam has been shown to produce anxiolytic-, hypnotic-, amnestic-, and sedative-like effects. However, few studies are concerned about its anti-PTSD-like effects. The anti-PTSD-like effects of estazolam were evaluated by single prolonged stress animal model. After exposure to single prolonged stress, rats (Sprague-Dawley, male, 8 weeks) were administered by estazolam (0.5, 1 and 2 mg/kg, i.p.) from day 2 to 13 once daily. The behavioral assessments were performed during treatment with drugs. After the behavioral evaluation, the role of allopregnanolone in the anti-PTSD-like effects of estazolam was also evaluated via astrocyte cells and brain tissues (e.g. prefrontal cortex, hippocampus, and amygdala). The PTSD-like behavioral deficits were significantly blocked by estazolam (1 and 2 mg/kg, i.p.) without affecting locomotor activity. Consistently, the levels on allopregnanolone were increased by estazolam (1 and 2 mg/kg, i.p.) in prefrontal cortex, hippocampus, and amygdala. The levels of allopregnanolone were increased by sertraline (1 µmoL/L) and estazolam (4 µmoL/L), while the effects were antagonized by trilostane (1 µmoL/L) and finasteride (1 µmoL/L) in astrocyte cells, respectively. Collectively, the anxiety-like behavior deficits were ameliorated by estazolam in the single prolonged stress animal model that was associated with biosynthesis of allopregnanolone.

Section snippets

Background

Post-traumatic stress disorder (PTSD) is a serious psychiatry that may occur following experience or witnessing of life-threatening events (Sareen et al., 2014). The avoidance on stimuli could serve as reminders of events and induce fear (Pugh et al., 2015). Consensus regarding the nature of factors remains unclear, although the pathophysiology of PTSD has been widely researched.

Changed levels of serotonin (5-HT) are associated with PTSD pathophysiology (Liu et al., 2013). For instance, levels

Drugs

Fetal bovine serum (FBS) and Dulbecco's modified Eagle's medium (DMEM) were purchased from GIBCO (USA) and Invitrogen (USA), respectively. Estazolam, sertraline, trilostane and finasteride were dissolved in dimethyl sulfoxide (DMSO) (less than 0.1%).

Animals

Male Sprague-Dawley rats (Vital River Laboratory Animal Technology Company, China) weighing 200 ± 20 g were maintained in temperature- (23 ± 1 °C), and humidity- controlled (45–50%) condition. The total number of animals was 60 and 10 in each group.

Effects of estazolam on PTSD-associated contextual freezing behavior in contextual fear paradigm

The effects of estazolam on PTSD-associated freezing behavior were shown in Fig. 2. One-way ANOVA showed that freezing time (F5,54 = 11.20, p < 0.05) was significantly increased after exposure to single prolonged stress. However, consistent with the effects of sertraline (15 mg/kg, i.p.), elevated freezing time was markedly reversed by estazolam (1 and 2 mg/kg, i.p.). Accordingly, PTSD-associated contextual freezing behavior could be attenuated by estazolam in contextual fear paradigm.

Effects of estazolam on PTSD-associated anxiety-like behavior in elevated plus maze test

The

Discussion

The present study indicated that the anxiolytic-like behavioral deficits were ameliorated by estazolam without affecting locomotor activity following exposure to single prolonged stress. In addition, lowered levels on allopregnanolone were blocked by estazolam, suggesting anti-PTSD-like effects of estazolam were associated with biosynthesis of allopregnanolone.

PTSD-like behavioral deficits were induced by single prolonged stress, which was evidenced by the increased freezing time (Fig. 2) and

Conclusion

Summary, the anti-PTSD-like effects of estazolam are associated with biosynthesis of allopregnanolone. These findings promote the advancement in our knowledge regarding the importance of neurosteroid biosynthesis for anti-PTSD-like effects of estazolam.

Competing interests

The authors declare that they have no competing interests.

Acknowledgement

We thank Zhi-Kun Qiu and Ji-Sheng Chen for the literature investigation.

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