Often the language needed to communicate these sensations seems inadequate. Yet, interoceptive sensations may be critical for survival. pH might be one of a variety of signals that could Metabolism inhibitor produce interoceptive sensations by activating pH-sensitive receptors in the brain to evoke adaptive responses. The survival value of rapidly detecting CO2 to prevent suffocation seems clear. Nearly 20 years ago Donald Klein drew from this observation Inhibitors,research,lifescience,medical to hypothesize that the suffocation detection system might be falsely triggered to produce panic attacks.5 Conceivably, heightened pH sensitivity could constitute

such a false alarm. Summary We don’t yet know why panic attacks occur. Nor do we completely understand why those who suffer panic attacks are hypersensitive to panicogens. However, the potential ability of CO2 and lactate, the two most well-studied panicogens, to alter brain pH suggests that pH chemosensation could be instrumental. Acid-sensitive molecules are widely distributed in Inhibitors,research,lifescience,medical fear circuit structures and elsewhere in the brain. Consistent with this observation, a variety of brain sites have been implicated in pH chemosensation including brain stem respiratory nuclei, midbrain raphe neurons, hypothalamus, and amygdala. Inhibitors,research,lifescience,medical However, a number of questions

remain. For example, what specific role(s) do each of these pH-sensitive sites and pH-sensitive molecules play? Could there be additional sources of acidosis and pH fluctuation besides CO2 or lactate that might activate these chemosensory pathways? Finally, might genetic or epigenetic variability in chemosensation lead to panic disorder or other psychiatric and neurological illnesses? That we are now in a position Inhibitors,research,lifescience,medical to ask these questions is in itself a significant advance. As we continue to learn more about CO2 and pH chemosensation in the brain, the answers to these questions may be within

reach. Moreover, an improved understanding of pH signaling and dysregulation might very Inhibitors,research,lifescience,medical well lead to an entirely new avenue of therapeutic intervention. Acknowledgments The author thanks Drs Michael Welsh, George Richerson, Margaret Price, William Coryell, Jess Fiedorowicz, and Tom Brashers-Krug for discussions and helpful comments. Dr Wemmie’s work is supported by NIMH 1R01MH085724-01, NINDS 1R01NS0641 59-01 A109, Department of Veteran’s Affairs Merit Review Program, McKnight Endowment Fund for Neuroscience, and the DANA Foundation.
In recent years, the development of neuroimaging techniques such as high-resolution all magnetic resonance imaging (MRI), functional magnetic resonance imaging (fMRI), positron emission tomography (PET), or single photon emission tomography (SPECT) has promoted the identification of structural and functional characteristics underlying mental disorders to a great extent. In anxiety disorders, recent neuroimaging techniques have contributed greatly to diagnosis and treatment, and helped to shed light on the neurobiological basis of anxiety in general.