| dc.description.abstract | Panic disorder and premenstrual dysphoria are accompanied by intriguing abnormalities related to the control of respiration, including enhanced responsiveness to CO2 and enhanced respiratory variability. These aberrations do not seem to be shared by other psychiatric disorders, but appear to be relatively unique for panic disorder and premenstrual dysphoria. To elucidate why these patients display these aberrations in breathing hence might lead to an increased understanding of the nature of these conditions. The main purpose of the studies presented in this thesis was to increase our knowledge regarding the regulation of breathing in rat, with particular reference to aspects that might shed light on the respiratory abnormalities associated with panic disorder and premenstrual dysphoria. To this end, the effects on respiration of compounds known to elicit anxiety attacks in patients with panic disorder or premenstrual dysphoria were studied, as were those of serotonin reuptake inhibition - the most effective pharmacological principle for the treatment of panic disorder and premenstrual dysphoria - and serotonin depletion, respectively. Prompted by reports suggesting that angiotensin II may influence both respiration and anxiety, we also investigated the possible role of this transmitter in the regulation of respiratory variability in rat, as well as the possible association between a number of angiotensin-related genes and panic disorder in humans. Given the key role of sex steroids for the pathophysiology of premenstrual dysphoria, and the likely involvement of sex steroids also in panic disorder, studies regarding the influence of estrus cyclicity on respiration in rat were included as well. Observations: 1) Sodium lactate in concentrations known to elicit panic attacks in panic disorder was found to stimulate respiration in rat. 2) This lactate-induced hyperventilation was found to be estrus cycle-related; female rats hence displayed enhanced response in diestrus, i.e. the phase roughly corresponding to the premenstrual phase of the menstrual cycle, than in proestrus/estrus. 3) Serotonin depletion decreased respiratory rate and increased respiratory variability while treatment with a serotonin reuptake inhibitor, paroxetine, increased respiratory rate and - after long-term treatment - lowered CO2 sensitivity. 4) Rats displaying cycle-related variations in aggression, in a tentative animal model of premenstrual dysphoria, were found also to display cycle-related variations in respiration and an increased respiratory variability as compared to non-aggressive controls. 5) Like the respiratory response to sodium lactate, also CO2 sensitivity was found to be estrus cycle-related; female rats displaying enhanced response in diestrus. 6) Central antagonism of angiotensin II-receptors was found to reduce respiratory variability in rat. 7) Panic disorder in men was found to be associated with the I/D polymorphism in the ACE gene. Conclusions: Our findings lend support to the theory of Donald F Klein that chemoreceptor activation might be a key component of spontaneous as well as provoked panic attacks. The observation that both sodium lactate-induced and CO2-induced hyperventilation were estrus cycle-related may have bearing on the fact that women with premenstrual dysphoria display enhanced responsiveness to these compounds. Further, it is suggested that the respiratory abnormalities observed in panic disorder and premenstrual dysphoria partly may be due to alterations in serotonergic neurotransmission, and that an influence on brainstem regulation of respiration may contribute to the antipanic effect of serotonin reuptake inhibitors. Abnormal angiotensin II activity is suggested to be of importance for the aberrations in respiration and heart rate variability observed in panic disorder, and tentatively also for the proneness to experience panic. | en |
