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

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

Research output: Contribution to journalArticle

22 Scopus citations

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 (US)
Pages (from-to)1333-1347
Number of pages15
JournalNeuropsychopharmacology
Volume35
Issue number6
DOIs
StatePublished - May 1 2010

Keywords

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

ASJC Scopus subject areas

  • Pharmacology
  • Psychiatry and Mental health

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