Activation of the Orexin 1 Receptor is a Critical Component of CO2-Mediated Anxiety and Hypertension but not Bradycardia

Abstract

Acute hypercapnia (elevated arterial CO 2 /H + ) is a suffocation signal that is life threatening and rapidly mobilizes adaptive changes in breathing and behavioral arousal in order to restore acid-base homeostasis. Severe hypercapnia, seen in respiratory disorders (eg, asthma or bronchitis, chronic obstructive pulmonary disease (COPD)), also results in high anxiety and autonomic activation. Recent evidence has demonstrated that wake-promoting hypothalamic orexin (ORX: also known as hypocretin) neurons are highly sensitive to local changes in CO 2 /H + , and mice lacking prepro-ORX have blunted respiratory responses to hypercapnia. Furthermore, in a recent clinical study, ORX-A, which crosses blood-brain barrier easily, was dramatically increased in the plasma of patients with COPD and hypercapnic respiratory failure. This is consistent with a rodent model of COPD where chronic exposure to cigarette smoke led to a threefold increase in hypothalamic ORX-A expression. In the present study, we determined the role of ORX in the anxiety-like behavior and cardiorespiratory responses to acute exposure to a threshold panic challenge (ie, 20% CO 2 /normoxic gas). Exposing conscious rats to such hypercapnic, but not atmospheric air, resulted in respiratory, pressor, and bradycardic responses, as well as anxiety-like behavior and increased cellular c-Fos responses in ORX neurons. Systemically, pre-treating rats with a centrally active ORX1 receptor antagonist (30 mg/kg SB334867) attenuated hypercapnic gas-induced pressor and anxiety responses, without altering the robust bradycardia response, and only attenuated breathing responses at offset of the CO 2 challenge. Our results show that the ORX system has an important role in anxiety and sympathetic mobilization during hypercapnia. Furthermore, ORX1 receptor antagonists may be a therapeutic option rapidly treating increased anxiety and sympathetic drive seen during panic attacks and in hypercapnic states such as COPD.

Orexins and fear: implications for the treatment of anxiety disorders

“…Consistent with this, chronic exposure to cigarette smoke tripled hypothalamic orexin A expression in a rodent model of COPD [67]. In addition, rat exposure to hypercapnic air increased c-Fos expression in orexin neurons, and promoted anxietylike behavior, which was prevented by systemic injection of SB334867 [68]. These data provide new insights to support the potential interest in OX1R antagonists for treating panic disorders.…”

5-HT2A receptor activation is necessary for CO2-induced arousal

“…Other neuronal populations involved in sleep-wake regulation have chemoreceptive capabilities. These include noradrenergic neurons of the locus coeruleus (Pineda and Aghajanian 1997), histaminergic neurons of the tuberomammillary nucleus (Johnson et al 2005), and orexinergic neurons in the lateral hypothalamus (Johnson et al 2010(Johnson et al , 2012Williams et al 2007). Another chemosensitive region, the retrotrapezoid nucleus, may be involved in sleep-wake regulation (Abbott et al 2013;Guyenet and Abbott 2013).…”

Enhanced non-eupneic breathing following hypoxic, hypercapnic or hypoxic–hypercapnic gas challenges in conscious mice

“…In any experiment, it is pertinent to question whether a change in Rinx reflects the effects of a particular challenge on peripheral or central respiratory homeostatic mechanisms, altered behavioral/locomotor patterns, or effects on the level of arousal/anxiety, knowing for example that hypoxic (Roth et al, 2002; Kumar and Goyal, 2008a,b; Ninot, 2011) and hypercapnic (Battaglia and Ogliari, 2005; Johnson et al, 2012; Battaglia et al, 2014) challenges are anxiogenic stimuli in humans and mice. As mentioned above, our studies show that the marked increase in disordered breathing events (e.g., apneas, sighs) during the post-hypoxic phase are not obviously related to behavioral activity at specific times during this period but it is certainly possible that anxiety elicited during the hypoxic and/or hypercapnic challenges are intimately involved in the expression of breathing pattern upon return to room-air in C57BL6 mice, whereas this may not be the case for Swiss-Webster or B6AF1 mice which show little disordered breathing during the post-hypoxia phase.…”