Changes in central sodium and not osmolarity or lactate induce panic-like responses in a model of panic disorder

Andre I. Molosh, Philip Johnson, Stephanie D. Fitz, Joseph A. Dimicco, James P. Herman, Anantha Shekhar

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

Panic disorder is a severe anxiety disorder characterized by recurrent panic attacks that can be consistently provoked with intravenous (i.v.) infusions of hypertonic (0.5 M) sodium lactate (NaLac), yet the mechanism/CNS site by which this stimulus triggers panic attacks is unclear. Chronic inhibition of GABAergic synthesis in the dorsomedial hypothalamus/perifornical region (DMH/PeF) of rats induces a vulnerability to panic-like responses after i.v. infusion of 0.5 M NaLac, providing an animal model of panic disorder. Using this panic model, we previously showed that inhibiting the anterior third ventricle region (A3Vr; containing the organum vasculosum lamina terminalis, the median preoptic nucleus, and anteroventral periventricular nucleus) attenuates cardiorespiratory and behavioral responses elicited by i.v. infusions of NaLac. In this study, we show that i.v. infusions of 0.5 M NaLac or sodium chloride, but not iso-osmolar D-mannitol, increased anxiety (decreased social interaction) behaviors, heart rate, and blood pressure responses. Using whole-cell patch-clamp preparations, we also show that bath applications of NaLac (positive control), but not lactic acid (lactate stimulus) or D-mannitol (osmolar stimulus), increases the firing rates of neurons in the A3Vr, which are retrogradely labeled from the DMH/PeF and which are most likely glutamatergic based on a separate study using retrograde tracing from the DMH/PeF in combination with in situ hybridization for vesicular glutamate transporter 2. These data show that hypertonic sodium, but not hyper-osmolarity or changes in lactate, is the key stimulus that provokes panic attacks in panic disorder, and is consistent with human studies.

Original languageEnglish
Pages (from-to)1333-1347
Number of pages15
JournalNeuropsychopharmacology
Volume35
Issue number6
DOIs
StatePublished - May 2010

Fingerprint

Panic
Panic Disorder
Osmolar Concentration
Lactic Acid
Sodium
Intravenous Infusions
Hypothalamus
Mannitol
Vesicular Glutamate Transport Protein 2
Sodium Lactate
Anterior Hypothalamus
Third Ventricle
Preoptic Area
Interpersonal Relations
Anxiety Disorders
Baths
Sodium Chloride
In Situ Hybridization
Anxiety
Animal Models

Keywords

  • Anxiety
  • DMH
  • Hypothalamus
  • OVLT
  • Panic
  • Sodium lactate

ASJC Scopus subject areas

  • Pharmacology
  • Psychiatry and Mental health

Cite this

Changes in central sodium and not osmolarity or lactate induce panic-like responses in a model of panic disorder. / Molosh, Andre I.; Johnson, Philip; Fitz, Stephanie D.; Dimicco, Joseph A.; Herman, James P.; Shekhar, Anantha.

In: Neuropsychopharmacology, Vol. 35, No. 6, 05.2010, p. 1333-1347.

Research output: Contribution to journalArticle

Molosh, Andre I. ; Johnson, Philip ; Fitz, Stephanie D. ; Dimicco, Joseph A. ; Herman, James P. ; Shekhar, Anantha. / Changes in central sodium and not osmolarity or lactate induce panic-like responses in a model of panic disorder. In: Neuropsychopharmacology. 2010 ; Vol. 35, No. 6. pp. 1333-1347.
@article{55d33472d3a445e78c4f9d0f9ec7c29e,
title = "Changes in central sodium and not osmolarity or lactate induce panic-like responses in a model of panic disorder",
abstract = "Panic disorder is a severe anxiety disorder characterized by recurrent panic attacks that can be consistently provoked with intravenous (i.v.) infusions of hypertonic (0.5 M) sodium lactate (NaLac), yet the mechanism/CNS site by which this stimulus triggers panic attacks is unclear. Chronic inhibition of GABAergic synthesis in the dorsomedial hypothalamus/perifornical region (DMH/PeF) of rats induces a vulnerability to panic-like responses after i.v. infusion of 0.5 M NaLac, providing an animal model of panic disorder. Using this panic model, we previously showed that inhibiting the anterior third ventricle region (A3Vr; containing the organum vasculosum lamina terminalis, the median preoptic nucleus, and anteroventral periventricular nucleus) attenuates cardiorespiratory and behavioral responses elicited by i.v. infusions of NaLac. In this study, we show that i.v. infusions of 0.5 M NaLac or sodium chloride, but not iso-osmolar D-mannitol, increased anxiety (decreased social interaction) behaviors, heart rate, and blood pressure responses. Using whole-cell patch-clamp preparations, we also show that bath applications of NaLac (positive control), but not lactic acid (lactate stimulus) or D-mannitol (osmolar stimulus), increases the firing rates of neurons in the A3Vr, which are retrogradely labeled from the DMH/PeF and which are most likely glutamatergic based on a separate study using retrograde tracing from the DMH/PeF in combination with in situ hybridization for vesicular glutamate transporter 2. These data show that hypertonic sodium, but not hyper-osmolarity or changes in lactate, is the key stimulus that provokes panic attacks in panic disorder, and is consistent with human studies.",
keywords = "Anxiety, DMH, Hypothalamus, OVLT, Panic, Sodium lactate",
author = "Molosh, {Andre I.} and Philip Johnson and Fitz, {Stephanie D.} and Dimicco, {Joseph A.} and Herman, {James P.} and Anantha Shekhar",
year = "2010",
month = "5",
doi = "10.1038/npp.2010.2",
language = "English",
volume = "35",
pages = "1333--1347",
journal = "Neuropsychopharmacology",
issn = "0893-133X",
publisher = "Nature Publishing Group",
number = "6",

}

TY - JOUR

T1 - Changes in central sodium and not osmolarity or lactate induce panic-like responses in a model of panic disorder

AU - Molosh, Andre I.

AU - Johnson, Philip

AU - Fitz, Stephanie D.

AU - Dimicco, Joseph A.

AU - Herman, James P.

AU - Shekhar, Anantha

PY - 2010/5

Y1 - 2010/5

N2 - Panic disorder is a severe anxiety disorder characterized by recurrent panic attacks that can be consistently provoked with intravenous (i.v.) infusions of hypertonic (0.5 M) sodium lactate (NaLac), yet the mechanism/CNS site by which this stimulus triggers panic attacks is unclear. Chronic inhibition of GABAergic synthesis in the dorsomedial hypothalamus/perifornical region (DMH/PeF) of rats induces a vulnerability to panic-like responses after i.v. infusion of 0.5 M NaLac, providing an animal model of panic disorder. Using this panic model, we previously showed that inhibiting the anterior third ventricle region (A3Vr; containing the organum vasculosum lamina terminalis, the median preoptic nucleus, and anteroventral periventricular nucleus) attenuates cardiorespiratory and behavioral responses elicited by i.v. infusions of NaLac. In this study, we show that i.v. infusions of 0.5 M NaLac or sodium chloride, but not iso-osmolar D-mannitol, increased anxiety (decreased social interaction) behaviors, heart rate, and blood pressure responses. Using whole-cell patch-clamp preparations, we also show that bath applications of NaLac (positive control), but not lactic acid (lactate stimulus) or D-mannitol (osmolar stimulus), increases the firing rates of neurons in the A3Vr, which are retrogradely labeled from the DMH/PeF and which are most likely glutamatergic based on a separate study using retrograde tracing from the DMH/PeF in combination with in situ hybridization for vesicular glutamate transporter 2. These data show that hypertonic sodium, but not hyper-osmolarity or changes in lactate, is the key stimulus that provokes panic attacks in panic disorder, and is consistent with human studies.

AB - Panic disorder is a severe anxiety disorder characterized by recurrent panic attacks that can be consistently provoked with intravenous (i.v.) infusions of hypertonic (0.5 M) sodium lactate (NaLac), yet the mechanism/CNS site by which this stimulus triggers panic attacks is unclear. Chronic inhibition of GABAergic synthesis in the dorsomedial hypothalamus/perifornical region (DMH/PeF) of rats induces a vulnerability to panic-like responses after i.v. infusion of 0.5 M NaLac, providing an animal model of panic disorder. Using this panic model, we previously showed that inhibiting the anterior third ventricle region (A3Vr; containing the organum vasculosum lamina terminalis, the median preoptic nucleus, and anteroventral periventricular nucleus) attenuates cardiorespiratory and behavioral responses elicited by i.v. infusions of NaLac. In this study, we show that i.v. infusions of 0.5 M NaLac or sodium chloride, but not iso-osmolar D-mannitol, increased anxiety (decreased social interaction) behaviors, heart rate, and blood pressure responses. Using whole-cell patch-clamp preparations, we also show that bath applications of NaLac (positive control), but not lactic acid (lactate stimulus) or D-mannitol (osmolar stimulus), increases the firing rates of neurons in the A3Vr, which are retrogradely labeled from the DMH/PeF and which are most likely glutamatergic based on a separate study using retrograde tracing from the DMH/PeF in combination with in situ hybridization for vesicular glutamate transporter 2. These data show that hypertonic sodium, but not hyper-osmolarity or changes in lactate, is the key stimulus that provokes panic attacks in panic disorder, and is consistent with human studies.

KW - Anxiety

KW - DMH

KW - Hypothalamus

KW - OVLT

KW - Panic

KW - Sodium lactate

UR - http://www.scopus.com/inward/record.url?scp=77951128416&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77951128416&partnerID=8YFLogxK

U2 - 10.1038/npp.2010.2

DO - 10.1038/npp.2010.2

M3 - Article

C2 - 20130534

AN - SCOPUS:77951128416

VL - 35

SP - 1333

EP - 1347

JO - Neuropsychopharmacology

JF - Neuropsychopharmacology

SN - 0893-133X

IS - 6

ER -