Valutazione delle variazioni plasmatiche dei neurosteroidi in soggetti sani durante test con CO2 al 7%: possibile modello sperimentale per la valutazione di nuovi farmaci ad azione ansiolitica

Dysregulation of the hypothalamic-pituitary-adrenal axis (HPA) and alteration of neurosteroids (NS) secretion may play a role in panic disorder, however studies in patients with panic disorders have produced inconsistent results. The objective of the present study is to clarify the role of neurosteroids and cortisol in healthy subjects undergoing a CO2 inhalation test. In particular we evaluated: 1) the changes in neurosteroids and cortisol plasma levels in “responders” and “non-responders” to the CO2 test; 2) the differences, if any, in NS and cortisol secretion between the two subgroups of “responders” and “non-responders”; 3) the correlation between symptoms and NS and cortisol plasma levels in the “responder” subgroup. A total of 58 subjects (17 male and 42 female) “responder” to a CO2 challange, were recruited in two studies performed according to a three way crossover, randomized, incomplete block, placebo controlled design. In three different study occasion, each subject received placebo, an active compound and an experimental drug before undergoing a test with 7% CO2 . Blood samples for concentration evaluation of progesterone, allopregnenolone, tetrahydrodeoxycorticosterone (THDOC), dehydroepiandrosterone (DHEA) and cortisol were collected at six time-points before and up to 70 minutes after the end of CO2 inhalation. The present study is focused on data collected during placebo study session. The main results were: THDOC concentration increased after challenge only in “non-responder” reaching the maximum value (? 30%, CI 7%/58%; 1.156 vs 0.890, p<0.01) 10 minutes after the end of CO2 inhalation; cortisol increased after challenge in both “responder” and “non-responder”, but only in the last group it showed statistical significant changes at end CO2 (? 47%, CI 15%/88%; 97.454 vs 66.166, p<0.01), at 10 and 30 minutes after the test (? 64%, CI 27%/112%; 108.552 vs 66.166, p<0.001; ? 59%, CI 27%/99%; 105.038 vs 66.166, p<0.001 respectively); in “non-responder” positive correlation was found between cortisolemia variation and ??of PSL III-R score. The increase in cortisol concentration seems to confirm the HPA response after 7% CO2 inhalation, more evident in the “non-responder” subgroup. The increase in THDOC might be a consequence of HPA axis activation following CO2 test and might contribute to the termination of the anxiety/stress response following challenge through enhancement of GABAA receptor function. Our data confirm that cortisol is an anxiogenic hormone, but it remains to be clarified whether induced panic-like attack is initially accompanied by major HPA axis activation or whether other stress-responsive systems (i.e. noradrenergic) underlie the CO2 challenge response.