An animal model of panic vulnerability with chronic disinhibition of the dorsomedial/perifornical hypothalamus

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Abstract

Panic disorder (PD) is a severe anxiety disorder characterized by susceptibility to induction of panic attacks by subthreshold interoceptive stimuli such as sodium lactate infusions or hypercapnia induction. Here we review a model of panic vulnerability in rats involving chronic inhibition of GABAergic tone in the dorsomedial/perifornical hypothalamic (DMH/PeF) region that produces enhanced anxiety and freezing responses in fearful situations, as well as a vulnerability to displaying acute panic-like increases in cardioexcitation, respiration activity and "flight" associated behavior following subthreshold interoceptive stimuli that do not elicit panic responses in control rats. This model of panic vulnerability was developed over 15years ago and has provided an excellent preclinical model with robust face, predictive and construct validity. The model recapitulates many of the phenotypic features of panic attacks associated with human panic disorder (face validity) including greater sensitivity to panicogenic stimuli demonstrated by sudden onset of anxiety and autonomic activation following an administration of a sub-threshold (i.e., do not usually induce panic in healthy subjects) stimulus such as sodium lactate, CO2, or yohimbine. The construct validity is supported by several key findings; DMH/PeF neurons regulate behavioral and autonomic components of a normal adaptive panic response, as well as being implicated in eliciting panic-like responses in humans. Additionally, patients with PD have deficits in central GABA activity and pharmacological restoration of central GABA activity prevents panic attacks, consistent with this model. The model's predictive validity is demonstrated by not only showing panic responses to several panic-inducing agents that elicit panic in patients with PD, but also by the positive therapeutic responses to clinically used agents such as alprazolam and antidepressants that attenuate panic attacks in patients. More importantly, this model has been utilized to discover novel drugs such as group II metabotropic glutamate agonists and a new class of translocator protein enhancers of GABA, both of which subsequently showed anti-panic properties in clinical trials. All of these data suggest that this preparation provides a strong preclinical model of some forms of human panic disorders.

Original languageEnglish
Pages (from-to)686-698
Number of pages13
JournalPhysiology and Behavior
Volume107
Issue number5
DOIs
StatePublished - Dec 5 2012

Fingerprint

Panic
Panic Disorder
Hypothalamus
Animal Models
Dimenhydrinate
Sodium Lactate
gamma-Aminobutyric Acid
Vulnerability
Animal Model
Anxiety
Alprazolam
Excitatory Amino Acid Agonists
Yohimbine
Hypercapnia
Anxiety Disorders
Reproducibility of Results
Freezing
Antidepressive Agents
Healthy Volunteers
Respiration

Keywords

  • Amygdala
  • Animal model
  • Anxiety
  • BNST
  • CCK
  • Cholecystokinin
  • CRF
  • DMH
  • Dorsomedial hypothalamus
  • Fear
  • GABA
  • Glutamate
  • Hypercapnia
  • Hypothalamus
  • L-allylglycine
  • Lateral septum
  • Locus coeruleus
  • Norepinephrine
  • Orexin
  • Panic
  • PeF
  • Perifornical
  • Raphe
  • Serotonin
  • Sodium lactate
  • Yohimbine

ASJC Scopus subject areas

  • Behavioral Neuroscience
  • Experimental and Cognitive Psychology
  • Philosophy

Cite this

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title = "An animal model of panic vulnerability with chronic disinhibition of the dorsomedial/perifornical hypothalamus",
abstract = "Panic disorder (PD) is a severe anxiety disorder characterized by susceptibility to induction of panic attacks by subthreshold interoceptive stimuli such as sodium lactate infusions or hypercapnia induction. Here we review a model of panic vulnerability in rats involving chronic inhibition of GABAergic tone in the dorsomedial/perifornical hypothalamic (DMH/PeF) region that produces enhanced anxiety and freezing responses in fearful situations, as well as a vulnerability to displaying acute panic-like increases in cardioexcitation, respiration activity and {"}flight{"} associated behavior following subthreshold interoceptive stimuli that do not elicit panic responses in control rats. This model of panic vulnerability was developed over 15years ago and has provided an excellent preclinical model with robust face, predictive and construct validity. The model recapitulates many of the phenotypic features of panic attacks associated with human panic disorder (face validity) including greater sensitivity to panicogenic stimuli demonstrated by sudden onset of anxiety and autonomic activation following an administration of a sub-threshold (i.e., do not usually induce panic in healthy subjects) stimulus such as sodium lactate, CO2, or yohimbine. The construct validity is supported by several key findings; DMH/PeF neurons regulate behavioral and autonomic components of a normal adaptive panic response, as well as being implicated in eliciting panic-like responses in humans. Additionally, patients with PD have deficits in central GABA activity and pharmacological restoration of central GABA activity prevents panic attacks, consistent with this model. The model's predictive validity is demonstrated by not only showing panic responses to several panic-inducing agents that elicit panic in patients with PD, but also by the positive therapeutic responses to clinically used agents such as alprazolam and antidepressants that attenuate panic attacks in patients. More importantly, this model has been utilized to discover novel drugs such as group II metabotropic glutamate agonists and a new class of translocator protein enhancers of GABA, both of which subsequently showed anti-panic properties in clinical trials. All of these data suggest that this preparation provides a strong preclinical model of some forms of human panic disorders.",
keywords = "Amygdala, Animal model, Anxiety, BNST, CCK, Cholecystokinin, CRF, DMH, Dorsomedial hypothalamus, Fear, GABA, Glutamate, Hypercapnia, Hypothalamus, L-allylglycine, Lateral septum, Locus coeruleus, Norepinephrine, Orexin, Panic, PeF, Perifornical, Raphe, Serotonin, Sodium lactate, Yohimbine",
author = "Philip Johnson and Anantha Shekhar",
year = "2012",
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pages = "686--698",
journal = "Physiology and Behavior",
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T1 - An animal model of panic vulnerability with chronic disinhibition of the dorsomedial/perifornical hypothalamus

AU - Johnson, Philip

AU - Shekhar, Anantha

PY - 2012/12/5

Y1 - 2012/12/5

N2 - Panic disorder (PD) is a severe anxiety disorder characterized by susceptibility to induction of panic attacks by subthreshold interoceptive stimuli such as sodium lactate infusions or hypercapnia induction. Here we review a model of panic vulnerability in rats involving chronic inhibition of GABAergic tone in the dorsomedial/perifornical hypothalamic (DMH/PeF) region that produces enhanced anxiety and freezing responses in fearful situations, as well as a vulnerability to displaying acute panic-like increases in cardioexcitation, respiration activity and "flight" associated behavior following subthreshold interoceptive stimuli that do not elicit panic responses in control rats. This model of panic vulnerability was developed over 15years ago and has provided an excellent preclinical model with robust face, predictive and construct validity. The model recapitulates many of the phenotypic features of panic attacks associated with human panic disorder (face validity) including greater sensitivity to panicogenic stimuli demonstrated by sudden onset of anxiety and autonomic activation following an administration of a sub-threshold (i.e., do not usually induce panic in healthy subjects) stimulus such as sodium lactate, CO2, or yohimbine. The construct validity is supported by several key findings; DMH/PeF neurons regulate behavioral and autonomic components of a normal adaptive panic response, as well as being implicated in eliciting panic-like responses in humans. Additionally, patients with PD have deficits in central GABA activity and pharmacological restoration of central GABA activity prevents panic attacks, consistent with this model. The model's predictive validity is demonstrated by not only showing panic responses to several panic-inducing agents that elicit panic in patients with PD, but also by the positive therapeutic responses to clinically used agents such as alprazolam and antidepressants that attenuate panic attacks in patients. More importantly, this model has been utilized to discover novel drugs such as group II metabotropic glutamate agonists and a new class of translocator protein enhancers of GABA, both of which subsequently showed anti-panic properties in clinical trials. All of these data suggest that this preparation provides a strong preclinical model of some forms of human panic disorders.

AB - Panic disorder (PD) is a severe anxiety disorder characterized by susceptibility to induction of panic attacks by subthreshold interoceptive stimuli such as sodium lactate infusions or hypercapnia induction. Here we review a model of panic vulnerability in rats involving chronic inhibition of GABAergic tone in the dorsomedial/perifornical hypothalamic (DMH/PeF) region that produces enhanced anxiety and freezing responses in fearful situations, as well as a vulnerability to displaying acute panic-like increases in cardioexcitation, respiration activity and "flight" associated behavior following subthreshold interoceptive stimuli that do not elicit panic responses in control rats. This model of panic vulnerability was developed over 15years ago and has provided an excellent preclinical model with robust face, predictive and construct validity. The model recapitulates many of the phenotypic features of panic attacks associated with human panic disorder (face validity) including greater sensitivity to panicogenic stimuli demonstrated by sudden onset of anxiety and autonomic activation following an administration of a sub-threshold (i.e., do not usually induce panic in healthy subjects) stimulus such as sodium lactate, CO2, or yohimbine. The construct validity is supported by several key findings; DMH/PeF neurons regulate behavioral and autonomic components of a normal adaptive panic response, as well as being implicated in eliciting panic-like responses in humans. Additionally, patients with PD have deficits in central GABA activity and pharmacological restoration of central GABA activity prevents panic attacks, consistent with this model. The model's predictive validity is demonstrated by not only showing panic responses to several panic-inducing agents that elicit panic in patients with PD, but also by the positive therapeutic responses to clinically used agents such as alprazolam and antidepressants that attenuate panic attacks in patients. More importantly, this model has been utilized to discover novel drugs such as group II metabotropic glutamate agonists and a new class of translocator protein enhancers of GABA, both of which subsequently showed anti-panic properties in clinical trials. All of these data suggest that this preparation provides a strong preclinical model of some forms of human panic disorders.

KW - Amygdala

KW - Animal model

KW - Anxiety

KW - BNST

KW - CCK

KW - Cholecystokinin

KW - CRF

KW - DMH

KW - Dorsomedial hypothalamus

KW - Fear

KW - GABA

KW - Glutamate

KW - Hypercapnia

KW - Hypothalamus

KW - L-allylglycine

KW - Lateral septum

KW - Locus coeruleus

KW - Norepinephrine

KW - Orexin

KW - Panic

KW - PeF

KW - Perifornical

KW - Raphe

KW - Serotonin

KW - Sodium lactate

KW - Yohimbine

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U2 - 10.1016/j.physbeh.2012.03.016

DO - 10.1016/j.physbeh.2012.03.016

M3 - Article

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JO - Physiology and Behavior

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