A key role for orexin in panic anxiety

Johnson, Philip L.; Truitt, William A.; Fitz, Stephanie D.; Minick, Pamela; Dietrich, Amy D.; Sanghani, Sonal P.; Träskman‐Bendz, Lil; Goddard, Andrew W.; Brundin, Lena; Shekhar, Anantha

doi:10.1038/nm.2075

Cited by 352 publications

(354 citation statements)

References 31 publications

(52 reference statements)

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“…Hypercarbic gas also increased cellular responses (ie, increased c-Fos expression) in the ORX neurons in the DMH/PeF, but not in the adjacent LH. In support of a role of ORX, systemically pretreating rats with a panicolytic dose (Johnson et al, 2010) of an ORX1 receptor antagonist (known to cross the blood-brain barrier; Ishii et al, 2005) before the hypercapnic challenge blocked pressor responses and attenuated anxiety-like behavior responses. Surprisingly, hypercarbic gas-induced bradycardia were unaffected by the ORX1 receptor antagonist.…”

Section: Discussionmentioning

confidence: 99%

“…However, 30 min before the hypercarbic gas challenge rats were injected with vehicle (0.2 ml/ 100 g volume dimethyl sulfoxide (DMSO)) or a dose of an ORX1 receptor antagonist (30 mg/kg SB334867, Tocris Bioscience, Bristol, UK, in 0.2 ml/100 g volume DMSO, i.p.) that blocks stress-induced anxiety-like behavior and panic-associated cardioexcitatory responses without inducing somnolence (Johnson et al, 2010). This drug crosses the blood-brain barrier (Ishii et al, 2005) and does not alter MAP, HR, or locomotor activity in control rats (Johnson et al, 2010).…”

Section: Experiments 3: Effects Of An Orx1 Antagonist On Hypercarbic Gmentioning

confidence: 99%

“…that blocks stress-induced anxiety-like behavior and panic-associated cardioexcitatory responses without inducing somnolence (Johnson et al, 2010). This drug crosses the blood-brain barrier (Ishii et al, 2005) and does not alter MAP, HR, or locomotor activity in control rats (Johnson et al, 2010). Blood pressure, HR, locomotor activity, number of fecal pellets, and anxiety-like behavior were assessed as described in experiment 1.…”

Section: Experiments 3: Effects Of An Orx1 Antagonist On Hypercarbic Gmentioning

confidence: 99%

“…Compared with ORX-B, ORX-A binds with a higher affinity to the ORX1 receptor, which is the receptor targeted here (for review, see Sakurai, 2007). This ORX system is critical for maintaining wakefulness (for review, see Sakurai, 2007) and a hyperactive ORX system is linked to: a rodent model of COPD (Liu et al, 2010); clinical COPD with hypercapnic respiratory disorder (Zhu et al, 2011); and anxiety-and panic-vulnerability in rats and humans (Johnson et al, 2010). Furthermore, during wakefulness prepro-ORX knockout mice have blunted respiratory responses to 5-10% hypercarbic gas exposure, and injecting wild-type mice with an ORX1 receptor antagonist attenuates hypercapnic-induced respiratory responses (Deng et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

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Activation of the Orexin 1 Receptor is a Critical Component of CO2-Mediated Anxiety and Hypertension but not Bradycardia

Johnson

Samuels

Fitz

et al. 2012

Neuropsychopharmacol

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Acute hypercapnia (elevated arterial CO 2 /H + ) is a suffocation signal that is life threatening and rapidly mobilizes adaptive changes in breathing and behavioral arousal in order to restore acid-base homeostasis. Severe hypercapnia, seen in respiratory disorders (eg, asthma or bronchitis, chronic obstructive pulmonary disease (COPD)), also results in high anxiety and autonomic activation. Recent evidence has demonstrated that wake-promoting hypothalamic orexin (ORX: also known as hypocretin) neurons are highly sensitive to local changes in CO 2 /H + , and mice lacking prepro-ORX have blunted respiratory responses to hypercapnia. Furthermore, in a recent clinical study, ORX-A, which crosses blood-brain barrier easily, was dramatically increased in the plasma of patients with COPD and hypercapnic respiratory failure. This is consistent with a rodent model of COPD where chronic exposure to cigarette smoke led to a threefold increase in hypothalamic ORX-A expression. In the present study, we determined the role of ORX in the anxiety-like behavior and cardiorespiratory responses to acute exposure to a threshold panic challenge (ie, 20% CO 2 /normoxic gas). Exposing conscious rats to such hypercapnic, but not atmospheric air, resulted in respiratory, pressor, and bradycardic responses, as well as anxiety-like behavior and increased cellular c-Fos responses in ORX neurons. Systemically, pre-treating rats with a centrally active ORX1 receptor antagonist (30 mg/kg SB334867) attenuated hypercapnic gas-induced pressor and anxiety responses, without altering the robust bradycardia response, and only attenuated breathing responses at offset of the CO 2 challenge. Our results show that the ORX system has an important role in anxiety and sympathetic mobilization during hypercapnia. Furthermore, ORX1 receptor antagonists may be a therapeutic option rapidly treating increased anxiety and sympathetic drive seen during panic attacks and in hypercapnic states such as COPD.

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Section: Discussionmentioning

confidence: 99%

Section: Experiments 3: Effects Of An Orx1 Antagonist On Hypercarbic Gmentioning

confidence: 99%

Section: Experiments 3: Effects Of An Orx1 Antagonist On Hypercarbic Gmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Activation of the Orexin 1 Receptor is a Critical Component of CO2-Mediated Anxiety and Hypertension but not Bradycardia

Johnson

Samuels

Fitz

et al. 2012

Neuropsychopharmacol

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“…They inhibit the increased mean arterial pressure, heart rate and freezing responses in rat models of panic disorder (Johnson et al, 2010).…”

Section: Mmandts 15mentioning

confidence: 98%

Overview of orexin/hypocretin system

Mieda

Sakurai

2012

Progress in Brain Research

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A series of recent studies has established the orexin/hypocretin system as a critical regulator of sleep/wake states. Its deficiency results in the sleep disorder narcolepsy in humans, dogs, and rodents. These findings have brought about the possibility of novel therapies for sleep disorders including narcolepsy and insomnia. Moreover, accumulating evidence indicates that the orexin/hypocretin system regulates sleep and wakefulness through interactions with neuronal systems that regulate emotion, reward, and energy homeostasis. Here, we briefly summarize the progress of orexin/hypocretin studies and future perspectives.

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Genetic Factors and Gene–Environment Interactions

Maron

Shlik

2014

The Wiley Handbook of Anxiety Disorders

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Previous genome-wide association studies (GWAS) have identified hundreds of genetic loci to be associated with body mass index (BMI) and risk of obesity. Genetic effects can differ between individuals depending on lifestyle or environmental factors due to gene-environment interactions. In this study, we examine gene-environment interactions in 362,496 unrelated participants with Caucasian ancestry from the UK Biobank resource. A total of 94 BMI-associated SNPs, selected from a previous GWAS on BMI, were used to construct weighted genetic scores for BMI (GS BMI). Linear regression modeling was used to estimate the effect of gene-environment interactions on BMI for 131 lifestyle factors related to: dietary habits, smoking and alcohol consumption, physical activity, socioeconomic status, mental health, sleeping patterns, as well as female-specific factors such as menopause and childbirth. In total, 15 lifestyle factors were observed to interact with GS BMI , of which alcohol intake frequency , usual walking pace, and Townsend deprivation index, a measure of socioeconomic status, were all highly significant (p = 1.45*10 −29 , p = 3.83*10 −26 , p = 4.66*10 −11 , respectively). Interestingly, the frequency of alcohol consumption, rather than the total weekly amount resulted in a significant interaction. The FTO locus was the strongest single locus interacting with any of the lifestyle factors. However, 13 significant interactions were also observed after omitting the FTO locus from the genetic score. Our analyses indicate that many lifestyle factors modify the genetic effects on BMI with some groups of individuals having more than double the effect of the genetic score. However, the underlying causal mechanisms of gene-environmental interactions are difficult to deduce from cross-sectional data alone and controlled experiments are required to fully characterise the causal factors. Author summary Genome-wide association studies (GWAS) have identified hundreds of genes as being associated with body mass index (BMI). How these genetic effects are modulated by lifestyle factors has not been extensively investigated previously. Here we utilise data from PLOS Genetics | https://doi.org/10.1371/journal.pgen.approximately 360,000 participants from the UK Biobank, aged 40-69 years old, to identify interactions between genetic and lifestyle factors in relation to BMI. We investigated 131 lifestyle factors, of which 15 influence the genetic effects on BMI. The most significant factors were those related to physical activity, alcohol consumption, and socioeconomic status. For example, the effect of a genetic score for BMI was almost twice as high in participants who reported never drinking alcohol compared to everyday drinkers. Similarly, the effect of the genetic score for BMI was 2.5 times higher in participants who reported having a slow walking pace compared to participants who reported having a brisk walking pace. Our results show that many lifestyle factors influence the genetic effects, which suggests that changing our lif...

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A key role for orexin in panic anxiety

Cited by 352 publications

References 31 publications

Activation of the Orexin 1 Receptor is a Critical Component of CO2-Mediated Anxiety and Hypertension but not Bradycardia

Activation of the Orexin 1 Receptor is a Critical Component of CO2-Mediated Anxiety and Hypertension but not Bradycardia

Overview of orexin/hypocretin system

Genetic Factors and Gene–Environment Interactions

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