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

Neuropsychopharmacology. 2010 May;35(6):1333-47. doi: 10.1038/npp.2010.2. Epub 2010 Feb 3.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Action Potentials / drug effects
  • Action Potentials / physiology
  • Animals
  • Cardiovascular Physiological Phenomena / drug effects*
  • Disease Models, Animal
  • Dorsomedial Hypothalamic Nucleus / drug effects
  • Dorsomedial Hypothalamic Nucleus / metabolism
  • Dorsomedial Hypothalamic Nucleus / physiopathology
  • Hypothalamus / drug effects*
  • Hypothalamus / metabolism
  • Hypothalamus / physiopathology
  • Male
  • Neurons / drug effects
  • Neurons / metabolism
  • Organ Culture Techniques
  • Osmolar Concentration
  • Panic Disorder / chemically induced*
  • Panic Disorder / metabolism
  • Panic Disorder / physiopathology
  • Patch-Clamp Techniques
  • Preoptic Area / drug effects
  • Preoptic Area / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Saline Solution, Hypertonic / pharmacology*
  • Sodium Chloride / pharmacology*
  • Sodium Lactate / pharmacology
  • Third Ventricle / anatomy & histology
  • Third Ventricle / drug effects*
  • Third Ventricle / physiopathology
  • gamma-Aminobutyric Acid / metabolism


  • Saline Solution, Hypertonic
  • Sodium Chloride
  • gamma-Aminobutyric Acid
  • Sodium Lactate