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A key role for orexin in panic anxiety

Abstract

Panic disorder is a severe anxiety disorder with recurrent, debilitating panic attacks. In individuals with panic disorder there is evidence of decreased central γ-aminobutyric acid (GABA) activity as well as marked increases in autonomic and respiratory responses after intravenous infusions of hypertonic sodium lactate1,2,3. In a rat model of panic disorder, chronic inhibition of GABA synthesis in the dorsomedial-perifornical hypothalamus of rats produces anxiety-like states and a similar vulnerability to sodium lactate–induced cardioexcitatory responses4,5,6,7,8,9. The dorsomedial-perifornical hypothalamus is enriched in neurons containing orexin (ORX, also known as hypocretin)10, which have a crucial role in arousal10,11, vigilance10 and central autonomic mobilization12, all of which are key components of panic. Here we show that activation of ORX-synthesizing neurons is necessary for developing a panic-prone state in the rat panic model, and either silencing of the hypothalamic gene encoding ORX (Hcrt) with RNAi or systemic ORX-1 receptor antagonists blocks the panic responses. Moreover, we show that human subjects with panic anxiety have elevated levels of ORX in the cerebrospinal fluid compared to subjects without panic anxiety. Taken together, our results suggest that the ORX system may be involved in the pathophysiology of panic anxiety and that ORX antagonists constitute a potential new treatment strategy for panic disorder.

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Figure 1: Effects of sodium lactate on ORX synthesizing neurons in rat panic model and effects of silencing ORX gene on panic responses.
Figure 2: Effects of ORX antagonists or alprazolam on panic responses in the rat panic model.
Figure 3: Further validation of an ORX antagonist on anxiety and panic asso-ciated behavior in the rat panic model.
Figure 4: Results of the human translational study.

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Acknowledgements

This work was supported by grants from the US National Institute of Mental Health (RO1 MH52619 and RO1 MH065702 to A.S.), the National Center for Research Resources (UL1RR025761 to A.S.), the Anxiety Disorders Association of America (Junior Faculty Research Award to P.L.J.), the National Alliance for Research on Schizophrenia and Depression (Young Investigator Award to P.L.J.), the Swedish Research Council (no. 14548) and the Swedish Government State Grants (L.T.-B. and L.B.).

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Contributions

A.S., P.L.J. and W.T. formulated the hypotheses and designed the studies. S.D.F. and P.L.J. performed telemetrical probe surgeries. SD.F. and P.L.J. scored all behavior, and S.D.F. performed all stereotaxic surgeries. P.L.J. performed the immunohistochemistry. P.E.M. and A.D. performed all RT-PCR assays with technical expertise from W.T. and S.S. P.L.J. and W.T. analyzed all rat data. L.T.-B. and L.B. were responsible for the human subject study, the ORX assays of the CSF samples and the analysis of the human data. P.L.J., W.T. and A.S. interpreted the data and collectively wrote the main draft of the article. P.L.J., W.T., .S.D.F., A.D., P.E.M., L.B., L.T.-B., A.W.G. and A.S. contributed to the writing of the manuscript and have approved the final version.

Corresponding author

Correspondence to Anantha Shekhar.

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Supplementary Methods, Supplementary Results, Supplementary Figures 1–5 and Supplementary Tables 1 and 2 (PDF 738 kb)

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Johnson, P., Truitt, W., Fitz, S. et al. A key role for orexin in panic anxiety. Nat Med 16, 111–115 (2010). https://doi.org/10.1038/nm.2075

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