Beyond the usual suspects: a cholinergic route for panic attacks

For unknown reasons and through poorly understood mechanisms, people at risk of panic attacks are hypersensitive to suffocative stimuli and experience hyperventilation and anxiety after exposure to heightened concentrations of carbon dioxide. Similarly to the physiological reflex response to hypercapnia in animals and man, the anxious response to carbon dioxide in people with panic disorder is at least partially controlled by the central muscarinic receptors. It is suggested here that some modifications of the cholinergic functions could underlie human individual differences in carbon dioxide sensitivity and proneness to experience panic attacks. The hypothesis is based upon experimental evidence that stressful and potentially harmful stimuli prime relatively long-lasting changes in cholinergic genes expression and cholinergic receptors' regulation. The adaptive sequels of these modifications include protection of the brain from overstimulation, and, at the level of the corticolimbic circuitries, promotion of passive avoidance and learning after stress. The extension of the same modifications to the cholinergic receptors involved in chemoception, however, could lower the threshold for reaction to suffocative stimuli, including carbon dioxide. The exaggerated sensitivity to carbon dioxide observed in humans suffering from panic attacks could then be thought of as an evolutionary cost of the involvement of the cholinergic system in shaping otherwise adaptive responses to stress and threatening stimuli.