Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
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.
惊恐障碍是一种严重的焦虑障碍，其特征是反复发作的惊恐发作，这些发作可以通过静脉（i.v.）输注高渗（0.5 M）乳酸钠（NaLac）持续引发，但触发惊恐发作的机制/中枢神经系统部位尚不清楚。在大鼠的背内侧下丘脑/peri 区域（DMH/PeF）慢性抑制 GABA 能合成会导致在静脉输注 0.5 M NaLac 后易发生类似惊恐的反应，提供了惊恐障碍的动物模型。使用这种惊恐模型，我们之前表明，抑制前第三脑室区域（A3Vr；包含血管体 lamina terminalis 器官、正中前视核和前腹侧脑室核）可减轻静脉输注 NaLac 引起的心肺和行为反应。在这项研究中，我们表明，静脉输注 0.5 M NaLac 或氯化钠，但不是等渗 D-甘露醇，会增加“焦虑”（社交互动减少）行为、心率和血压反应。使用全细胞膜片钳制备，我们还表明，NaLac（阳性对照）而不是乳酸（乳酸刺激物）或 D-甘露醇（等渗刺激物）的浴应用会增加 A3Vr 神经元的放电率，这些神经元是从 DMH/PeF 逆行标记的，并且基于从 DMH/PeF 逆行追踪与原位杂交相结合用于囊泡谷氨酸转运体 2 的单独研究，很可能是谷氨酸能的。这些数据表明，高渗钠，而不是高渗透压或乳酸的变化，是引发惊恐障碍惊恐发作的关键刺激物，与人类研究一致。
