Sex differences in anxiety disorders: Interactions between fear, stress, and gonadal hormones

This study evaluated the chronic effects of fluoxetine, a commonly prescribed SSRI antidepressant, on the peripheral and central levels of inflammatory cytokines including IL-1β, IL-6, TNF-α and IL-17 over a 4-interval in a rat model of chronic mild stress (CMS) which resembles the human experience of depression. Twenty-four Sprague-Dawley rats were randomly assigned to CMS+vehicle (n = 9), CMS+fluoxetine (n = 9) and the control (n = 6) groups. Sucrose preference and forced swim tests were performed to assess behavioral change. Blood samples were collected on day 0, 60, 90 and 120 for measurement of cytokine levels in plasma. On day 120, the brain was harvested and central level of cytokines was tested using Luminex. Four months of fluoxetine treatment resulted in changes in the sucrose preference and immobility time measurements, commensurate with antidepressant effects. The CMS+vehicle group exhibited elevated plasma levels of IL-1β, IL-17, and TNF-α on day 60 or 120. Rats treated with fluoxetine demonstrated lower IL-1β in plasma and brain after 90 and 120-day treatment respectively (p<0.05). There was a trend of reduction of IL-6 and TNF-α concentration. This study revealed the potential therapeutic effects of fluoxetine by reducing central and peripheral levels of IL-1β in the alleviation of depressive symptoms.

/pdf/chronic-administration-of-fluoxetine-and-pro-inflammatory-1copeoq5nj.pdf

Chronic administration of fluoxetine and pro-inflammatory cytokine change in a rat model of depression.

Dr. Athina Markou sought treatments for a common neural substrate shared by depression and drug dependence. Antagonists of corticotropin-releasing factor (CRF) receptors, a target of interest to her, have not reached the clinic despite strong preclinical rationale and sustained translational efforts. We explore potential causes for the failure of CRF1 antagonists and review recent findings concerning CRF-CRF1 systems in psychopathology. Potential causes for negative outcomes include (1) poor safety and efficacy of initial drug candidates due to bad pharmacokinetic and physicochemical properties, (2) specificity problems with preclinical screens, (3) the acute nature of screens vs. late-presenting patients, (4) positive preclinical results limited to certain models and conditions with dynamic CRF-CRF1 activation not homologous to tested patients, (5) repeated CRF1 activation-induced plasticity that reduces the importance of ongoing CRF1 agonist stimulation, and (6) therapeutic silencing which may need to address CRF2 receptor or CRF-binding protein molecules, constitutive CRF1 activity, or molecules that influence agonist-independent activity or to target structural regions other than the allosteric site bound by all drug candidates. We describe potential markers of activation towards individualized treatment, human genetic, and functional data that still implicate CRF1 systems in emotional disturbance, sex differences, and suggestive clinical findings for CRF1 antagonists in food craving and CRF-driven HPA-axis overactivation. The therapeutic scope of selective CRF1 antagonists now appears narrower than had been hoped. Yet, much remains to be learned about CRF’s role in the neurobiology of dysphoria and addiction and the potential for novel anti-CRF therapies therein.

/pdf/don-t-stress-about-crf-assessing-the-translational-failures-469mqaxl9s.pdf

Don't stress about CRF: assessing the translational failures of CRF 1 antagonists.

https://pure.knaw.nl/ws/files/9314478/Bao2019Ibroreports.pdf

The human hypothalamus in mood disorders: The HPA axis in the center.

Stress influences emotional learning and memory processes. These effects are thought to underlie stress-associated mental disorders. Sex differences in stress reactivity and in central nervous system stress sensitivity illustrate the important modulatory role of sex hormones. This Review outlines how stress hormones influence different stages of the fear conditioning process, such as fear acquisition, extinction, and retrieval. Results will be compared with findings on the impact of stress on episodic memory. The focus is on the available human data on sex differences and the impact sex hormones have on the stress effects on emotional learning and memory. It will become apparent that the menstrual cycle but also the intake of hormonal contraceptives modulates the impact of stress on brain and behavior. Additional basic research is needed for a deeper insight regarding the interplay between stress and sex hormones in emotion and cognition. In addition, new treatment options might be derived to optimize existing strategies such as exposure therapy, which relies on the principles of fear conditioning. © 2016 Wiley Periodicals, Inc.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/jnr.23811

Sex differences in stress effects on emotional learning

Sex differences in the stress response in SD rats.

https://pure.knaw.nl/ws/files/4083887/Lu2017eBiomedicine.pdf

Jing Lu

Papers

Sex differences in the stress response in SD rats.

Sexually Dimorphic Changes of Hypocretin (Orexin) in Depression

Effect of pentobarbital and isoflurane on acute stress response in rat.

Different stress-related gene expression in depression and suicide

Linking peripheral IL-6, IL-1β and hypocretin-1 with cognitive impairment from major depression