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Sex, Pramipexole and Tiagabine Affect Behavioral and Hormonal Response to Traumatic Stress in a Mouse Model of PTSD.

ABSTRACT: Posttraumatic stress disorder (PTSD) has been associated with abnormal regulation of the hypothalamic-pituitary-adrenal gland axis (HPA). Women demonstrate a more robust HPA response and are twice as likely to develop PTSD than men. The role of sex hormones in PTSD remains unclear. We investigated whether post-trauma chronic treatment with the GABA-ergic agent tiagabine and dopamine-mimetic pramipexole affected the behavioral outcome and plasma levels of corticosterone, testosterone, or 17β-estradiol in female and male mice. These medications were investigated due to their potential capacity to restore GABA-ergic and dopaminergic deficits in PTSD. Animals were exposed to a single prolonged stress procedure (mSPS). Following 13 days treatment with tiagabine (10 mg/kg) or pramipexole (1 mg/kg) once daily, the PTSD-like phenotype was examined in the fear conditioning paradigm. Plasma hormones were measured almost immediately following the conditioned fear assessment. We report that the exposure to mSPS equally enhanced conditioned fear in both sexes. However, while males demonstrated decreased plasma corticosterone, its increase was observed in females. Trauma elevated plasma testosterone in both sexes, but it had no significant effects on 17β-estradiol. Behavioral manifestation of trauma was reduced by pramipexole in both sexes and by tiagabine in females only. While neither compound affected corticosterone in stressed animals, testosterone levels were further enhanced by tiagabine in females. This study shows sex-dependent efficacy of tiagabine but not pramipexole in a mouse model of PTSD-like symptoms and a failure of steroid hormones' levels to predict PTSD treatment efficacy.

SUBMITTER: Malikowska-Racia N

PROVIDER: S-EPMC8277945 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundPost-traumatic stress disorder (PTSD) affects men and women differently. Not only are women twice as likely as men to develop PTSD, they experience different symptoms and comorbidities associated with PTSD. Yet the dearth of preclinical research on females leaves a notable gap in understanding the underlying neuropathology of this sex difference.MethodsUsing two standard measures of PTSD-like responses in rats, the acoustic startle response (ASR) and dexamethasone suppression test (DST), we tested the effects of traumatic stress in adult male and female rats using two rodent models of PTSD, single prolonged stress and predator exposure. We then examined the neural correlates underlying these responses with cFos and glucocorticoid receptor immunohistochemistry in brain regions implicated in the traumatic stress response.ResultsWe now report that adult male and female rats across two models of PTSD show consistent sex-specific responses that recapitulate fundamental differences of PTSD in men and women. Trauma-exposed males showed the well-established hyper-responsive phenotype of enhanced ASR and exaggerated negative feedback control of the hypothalamic-pituitary-adrenal axis, while the same traumatic event had little effect on these same measures in females. Dramatic sex differences in how trauma affected cFos and glucocorticoid receptor expression in the brain lend further support to the idea that the trauma response of male and female rats is fundamentally different.ConclusionsTwo standard measures, ASR and DST, might suggest that females are resilient to the effects of traumatic stress, but other measures make it clear that females are not resilient, but simply respond differently to trauma. The next important question to answer is why. We conclude that males and females show fundamentally different responses to trauma that do not simply reflect differences in resilience. The divergent effects of trauma in the brains of males and females begin to shed light on the neurobiological underpinnings of these sex differences, paving the way for improved diagnostics and therapeutics that effectively treat both men and women.

Project description:BackgroundSelf-stigma refers to the internalisation of negative societal views and stereotypes. Self-stigma has been well-characterised in the context of mental disorders such as schizophrenia but has received little attention in relation to post-traumatic stress disorder (PTSD).ObjectiveThis work aimed to determine the prevalence of self-stigma in a sample of adults with PTSD and to establish factors associated with the internalisation of stigma in this population.MethodParticipants were 194 adults (mean age 46.07 (SD = 12.39); 64.4% female; 96.6% white Caucasian; residing in the UK), who self-reported a diagnosis of PTSD and currently screened positive for the disorder according to the PTSD Checklist for DSM-5 (PCL-5). Structured interviews and validated self-report questionnaires were used to ascertain clinical and sociodemographic information for analysis.ResultsThe prevalence of self-stigma measured by the Internalized Stigma of Mental Illness Scale (ISMIS) was 41.2% (95% CI 34.24-48.22). There was no evidence of an association between self-stigma and gender (β = -2.975 (95% CI -7.046-1.097) p = .151), age (β = 0.007 (95% CI -0.152-0.165) p = .953), sexual trauma (β = 0.904 (95% CI -3.668-5.476) p = .697), military trauma (β = -0.571 (95% CI -4.027-7.287) p = .571). Self-stigma was associated with lower income and higher levels of anxiety (β = 5.722 (95% CI 2.922-8.522) p = <.001), depression (β = 6.937 (95% CI 4.287-9.588) p = <.000), and traumatic stress symptoms (β = 3.880 (95% CI 1.401-6.359) p = .002).ConclusionsThe results indicate that self-stigma may be a significant issue among people with a diagnosis of PTSD. Further work is needed to understand the long-term impact and to develop interventions to address the internalisation of stigma in this population.HighlightsThe prevalence of self-stigma among a sample of participants with PTSD was 41.2%.There was no evidence of an association between self-stigma and gender, age or sexual / military trauma.Self-stigma was associated with lower income and higher levels of anxiety, depression, and traumatic stress symptoms.

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Sex, Pramipexole and Tiagabine Affect Behavioral and Hormonal Response to Traumatic Stress in a Mouse Model of PTSD.

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