On the biology of premenstrual dysphoria and panic disorder

Sammanfattning: Premenstrual dysphoria (PMD) afflicts 7% of all women of fertile age, and is characterized by symptoms such as irritability, sadness, and mood swings, appearing regularly before menstruation, and being of such severity that they markedly reduce quality of life. The symptoms are dependent of sex steroids, and seem to be under the influence of serotonin, since they respond to treatment with serotonin reuptake inhibitors (SRIs). Panic disorder (PD) afflicts 3% of the population, and is characterized by anxiety attacks, often dominated by respiratory symptoms. PD is more common in women than in men, and fluctuations in levels of sex steroids have been reported to influence the symptom intensity. Like patients with PMD, subjects with PD respond to treatment with SRIs. PMD and PD also display other similarities; both diagnoses hence are associated with enhanced respiratory variability, and with an enhanced sensitivity to the anxiety-provoking effects of CO2 and lactate. One purpose of this work was to develop an animal model of premenstrual irritability, and to use this to elucidate the role of serotonin and sex steroids for this condition. In order to shed further light on the respiratory abnormalities characterizing both PMD and PD, and the possible role of the estrus cycle in this context, we also studied respiratory rate, tidal volume and respiratory variability in freely moving rats. Finally, a third purpose, prompted by the suggestion that progesterone, by influencing respiration, is involved in the pathophysiology of PD, was to examine to what extent PMD and PD are associated with polymorphisms in the progesterone receptor gene. Results: Some but not all female Wistar rat displayed aggressive behavior in the resident intruder paradigm during the non-receptive phase of the cycle. Like the symptoms of PMD, this behavior was abolished by ovariectomy, and reinstated - in rats that had displayed aggression before gonadectomy - by exogenous sex steroids. Treatment with two different SRIs was shown to reduce estrus cycle-related aggression; this effect was observed rapidly after drug administration, unabated during long-term treatment, and partially counteracted by a 5-HT1A antagonist. Tentatively corresponding to SRI-induced reduced in libido in humans, a reduction in sexual motivation was observed in SRI-treated rats. Respiratory rate was shown to be estrus cycle-dependent, but only in rats showing cycle-related aggression; these animals also displayed enhanced respiratory variability. Aggressive and non-aggressive rats also differed with respect to brain monoamine metabolism, but not with respect to sex steroids in serum. PD in women, but not PMD, was associated with a promoter polymorphism (G331A) in the progesterone receptor gene. Conclusion: It is suggested that estrus cycle-related aggression in a subgroup of female Wistar rats corresponds to premenstrual irritability. An enhanced brain responsiveness to sex steroids is suggested to influence both aggression and respiration, and may tentatively be due either to an increase in sex steroid receptor responsiveness or to a dysfunction in serotonergic neurons mediating or modulating the effects of sex steroids. The possible relevance of these findings and hypotheses for the biology of PD and PMD is being discussed.