Changes in central sodium and not osmolarity or lactate induce panic-like responses in a model of panic disorder.
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.
Molosh
Andre I
AI
Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Johnson
Philip L
PL
Fitz
Stephanie D
SD
Dimicco
Joseph A
JA
Herman
James P
JP
Shekhar
Anantha
A
D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D002320:Cardiovascular Physiological Phenomena / Q000187:drug effects*; D004195:Disease Models, Animal; D004302:Dorsomedial Hypothalamic Nucleus / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D007031:Hypothalamus / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009924:Organ Culture Techniques; D009994:Osmolar Concentration; D016584:Panic Disorder / Q000139:chemically induced* / Q000378:metabolism / Q000503:physiopathology; D018408:Patch-Clamp Techniques; D011301:Preoptic Area / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012462:Saline Solution, Hypertonic / Q000494:pharmacology*; D012965:Sodium Chloride / Q000494:pharmacology*; D019354:Sodium Lactate / Q000494:pharmacology; D020542:Third Ventricle / Q000033:anatomy & histology / Q000187:drug effects* / Q000503:physiopathology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D012462:Saline Solution, Hypertonic; D012965:Sodium Chloride; D005680:gamma-Aminobutyric Acid; D019354:Sodium Lactate