The contribution of orexins to sex differences in the stress response

Grafe, Laura A.; Bhatnagar, Seema

doi:10.1016/j.brainres.2018.07.026

Cited by 43 publications

(25 citation statements)

References 97 publications

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“…The clinical evidence implicating ORX in PD is important 11,51 and our results showing that NMS augments ORX A levels in the hypothalamus are consistent with clinical and preclinical data. A similar increase has been reported in males 18 but since regulation of ORX neurons likely differs between sexes 19,22 , testing this effect in females was necessary. ORX synthesis is activity-dependent and highly plastic 52 .…”

Section: Neonatal Maternal Separation Augments Orx Activation Under Bsupporting

confidence: 62%

“…The prevalence of PD is 2-3 fold greater in women than in men, yet most of our basic knowledge arises from experiments performed on males despite strong evidence indicating that endocrine regulation of ORX neurons is sex-specific 22,23 . This is an important issue because clinical observations point to an important role of ovarian hormones in the pathophysiology of PD.…”

Section: Introductionmentioning

confidence: 99%

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Disruption of estradiol regulation of orexin neurons: a novel mechanism in excessive ventilatory response to CO2 inhalation in a female rat model of panic disorder

et al. 2020

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Panic disorder (PD) is ~2 times more frequent in women. An excessive ventilatory response to CO2 inhalation is more likely during the premenstrual phase. While ovarian hormones appear important in the pathophysiology of PD, their role remains poorly understood as female animals are rarely used in pre-clinical studies. Using neonatal maternal separation (NMS) to induce a “PD-like” respiratory phenotype, we tested the hypothesis that NMS disrupts hormonal regulation of the ventilatory response to CO2 in female rats. We then determined whether NMS attenuates the inhibitory actions of 17-β estradiol (E2) on orexin neurons (ORX). Pups were exposed to NMS (3 h/day; postnatal day 3–12). The ventilatory response to CO2-inhalation was tested before puberty, across the estrus cycle, and following ovariectomy. Plasma E2 and hypothalamic ORXA were measured. The effect of an ORX1 antagonist (SB334867; 15 mg/kg) on the CO2 response was tested. Excitatory postsynaptic currents (EPSCs) were recorded from ORX neurons using whole-cell patch-clamp. NMS-related increase in the CO2 response was observed only when ovaries were functional; the largest ventilation was observed during proestrus. SB334867 blocked this effect. NMS augmented levels of ORXA in hypothalamus extracts. EPSC frequency varied according to basal plasma E2 levels across the estrus cycle in controls but not NMS. NMS reproduces developmental and cyclic changes of respiratory manifestations of PD. NMS disrupts the inhibitory actions of E2 on the respiratory network. Impaired E2-related inhibition of ORX neurons during proestrus is a novel mechanism in respiratory manifestations of PD in females.

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Section: Neonatal Maternal Separation Augments Orx Activation Under Bsupporting

confidence: 62%

Section: Introductionmentioning

confidence: 99%

Disruption of estradiol regulation of orexin neurons: a novel mechanism in excessive ventilatory response to CO2 inhalation in a female rat model of panic disorder

et al. 2020

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“…Another group has shown that administration of the OXA peptide in the cerebral ventricles elicits anxiety-like behaviors in both mice and rats ( Suzuki et al, 2005 ). There is also preclinical and clinical evidence that an enhanced level of orexin activity may contribute to the higher incidence of anxiety in females ( Grafe and Bhatnagar, 2020 ).…”

Section: Orexin Neurotransmission To the Pvt And Stress-induced Anxiementioning

confidence: 99%

The Paraventricular Nucleus of the Thalamus as an Integrating and Relay Node in the Brain Anxiety Network

Kirouac

2021

Front. Behav. Neurosci.

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The brain anxiety network is composed of a number of interconnected cortical regions that detect threats and execute appropriate defensive responses via projections to the shell of the nucleus accumbens (NAcSh), dorsolateral region of the bed nucleus of the stria terminalis (BSTDL) and lateral region of the central nucleus of the amygdala (CeL). The paraventricular nucleus of the thalamus (PVT) is anatomically positioned to integrate threat- and arousal-related signals from cortex and hypothalamus and then relay these signals to neural circuits in the NAcSh, BSTDL, and CeL that mediate defensive responses. This review describes the anatomical connections of the PVT that support the view that the PVT may be a critical node in the brain anxiety network. Experimental findings are reviewed showing that the arousal peptides orexins (hypocretins) act at the PVT to promote avoidance of potential threats especially following exposure of rats to a single episode of footshocks. Recent anatomical and experimental findings are discussed which show that neurons in the PVT provide divergent projections to subcortical regions that mediate defensive behaviors and that the projection to the NAcSh is critical for the enhanced social avoidance displayed in rats exposed to footshocks. A theoretical model is proposed for how the PVT integrates cortical and hypothalamic signals to modulate the behavioral responses associated with anxiety and other challenging situations.

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“…Finally, the results’ generalizability to females should also be assessed in the light of preclinical and clinical evidence for higher orexin system expression in females. 56 …”

Section: Discussionmentioning

confidence: 99%

Experimental Drugs for Panic Disorder: An Updated Systematic Review

Caldirola¹,

Alciati²,

Cuniberti³

et al. 2021

JEP

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Several effective pharmacological therapies for panic disorder (PD) are available, but they have some drawbacks, and unsatisfactory outcomes can occur. Expanding the variety of anti-panic medications may allow for improving PD treatment. The authors performed an updated systematic review of preclinical and clinical (Phase I–III) pharmacological studies to look for advances made in the last six years concerning novel-mechanism-based anti-panic compounds or using medications approved for nonpsychiatric medical conditions to treat PD. The study included seven published articles presenting a series of preclinical studies, two Phase I clinical studies with orexin receptor (OXR) antagonists, and two clinical studies investigating the effects of D-cycloserine (DCS) and xenon gas in individuals with PD. The latest preclinical findings confirmed and expanded previous promising indications of OXR1 antagonists as novel-mechanism-based anti-panic compounds. Translating preclinical research into clinical applications remains in the early stages. However, limited clinical findings suggested the selective OXR1 antagonist JNJ-61393115 may exert anti-panic effects in humans. Overall, OXR1 antagonists displayed a favorable profile of short-term safety and tolerability. Very preliminary suggestions of possible anti-panic effects of xenon gas emerged but need confirmation with more rigorous methodology. DCS did not seem promising as an enhancer of cognitive-behavioral therapy in PD. Future studies, including objective panic-related physiological parameters, such as respiratory measures, and expanding the use of panic vulnerability biomarkers, such as hypersensitivity to CO 2 panic provocation, may allow for more reliable conclusions about the anti-panic properties of new compounds.

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The contribution of orexins to sex differences in the stress response

Cited by 43 publications

References 97 publications

Disruption of estradiol regulation of orexin neurons: a novel mechanism in excessive ventilatory response to CO2 inhalation in a female rat model of panic disorder

Disruption of estradiol regulation of orexin neurons: a novel mechanism in excessive ventilatory response to CO2 inhalation in a female rat model of panic disorder

The Paraventricular Nucleus of the Thalamus as an Integrating and Relay Node in the Brain Anxiety Network

Experimental Drugs for Panic Disorder: An Updated Systematic Review

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