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.