Does the Brain Noradrenaline Network Mediate the Effects of the CO2 Challenge?

noradrenergic system and the hypothalamic-pituitary-adrenal (HPA) axis in the response to the hypercapnic inhalation challenge test. The issue is interesting since it is widely debated and still unclear. The authors report data from their own recent study showing that a single inhalation of 35% CO2 increases plasma cortisol levels and blood pressure in a sample of healthy volunteers and they propose that the noradrenaline network might be a key mediator of these responses. This proposal raises several questions. The mechanisms underlying the reaction to a CO2 challenge test are not necessarily the same in healthy subjects and in subjects with Panic Disorder (PD). Moreover, none of the subjects in the study panicked with 35% CO2 and thus the observed neuroendocrinological responses might be different from those of the panic attacks. To date, the data concerning the activation of the HPA axis during panic attacks are controversial but most of the studies show a lack of significant activation of HPA in subjects with PD. In particular, panicogenic agents such as sodium lactate, CO2, bicarbonate and doxapram are not accompanied by activation of the HPA axis (Abelson et al., 1996; Shina et al., 1999), whereas other agents, such as fenfluramine, yohimbine and metachlorophenylpiperazine, seem to be characterized by an involvement of HPA (Shina et al., 1999). The former group of agents provokes panic attacks with prominent respiratory symptoms whereas the latter does not provoke marked smothering sensations during attacks. This is in line with the idea that panic attacks, particularly those characterized by marked respirator symptoms, might be different from fear, stress and anticipatory anxiety involving the HPA axis (Shina et al., 1999) and might involve a specific underlying dysregulation in the respiratory system or in brainstem neuronal circuits regulating physiological homeostasis. Our team has recently compared the baseline respirator pattern in a sample of patients with PD and healthy subjects. We found a higher entropy in respiratory baseline patterns of patients with PD, indicating higher levels of complexity and irregularity in their respiratory function. Because anxiety state, severity of illness and individual variables did not influence the results, higher respiration irregularity appears to be a trait feature of patients with PD and could represent a vulnerability factor to panic attacks (Caldirola et al., 2003). Therefore, the 35% CO2 inhalation could stimulate neurobiological circuits in healthy subjects that differ from those in patients with PD. In patients with PD, the 35% CO2 inhalation could represent a trigger for a specific underlaying mechanism, perhaps involving a brainstem respirator network, whereas in healthy controls the 35% CO2 inhalation could represent a nonspecific stressful stimulus. In order to evaluate this idea, it would be useful to compare the plasma cortisol response to CO2 inhalation with that induced by insertion of an intravenous catheter in the sample of the study. Further studies are necessary to clarify the HPA axis function in patients with PDF during panicogenic challenges and during different stressful stimuli. Recent results from our team show that the noradrenergic system might be less relevant for the pathophysiogical mechanisms of panic than the serotonergic one. Anxiety reactivity to 35% CO2 inhalation in a sample of patients with PD after 1 week of treatment with paroxetine, a selective serotonin reuptake inhibitor, or reboxetine, a noradrenaline reuptake inhibitor, decreases significantly with both drugs but the decrease is significantly stronger in the group treated with paroxetine. Moreover, the rate of response of patients whose reactivity becomes negative after 1 week is significantly higher in the group treated with paroxetine than in the one treated with reboxetine. (Perna et al., 2003). The evaluation of clinical effects of a 12-week treatment with paroxetine or reboxetine in patients with PD shows a global improvement in both groups but a difference arises when comparing the Panic Associated Symptoms Scale (PASS) scores and the rate of good responders in the two groups. The patients treated with paroxetine show a significantly stronger reduction of panic attacks subscale score of PASS than patients treated with reboxetine, whereas neither group shows differences in the reduction of the avoidance and anticipatory anxiety subscales scores. Finally, the rate of good responders, defined as a reduction of at least 50% from baseline in both PASS total and Sheehan Disability Scale (SDS) scores at day 90, is greater in the paroxetine group than in the reboxetine one (Bertani et al., 2003). Although both serotonin and noradrenaline appear to play a role in the therapeutic effects of antipanic drugs, these results suggest a possible dissection for the three features of PD (i.e. panic attacks, anticipatory anxiety and avoidant behaviour) and a possible different role of the noradrenergic and serotonergic systems in the modulation of mechanisms underlying these features. The serotonergic system seems to modulate, particularly, the ‘core’ phenomenon of PD (i.e. the panic attack) whereas the noradrenergic one seems more to be involved in clinical features usually following the panic attacks (i.e. the anticipatory anxiety and the avoidant behaviour). Journal of Psychopharmacology 17(3) (2003) 263–264 ©2003 British Association for Psychopharmacology (ISSN 0269-8811) SAGE Publications, London, Thousand Oaks, CA and New Delhi 0269–8811[200309]17:3; 263–264; 034951