Respiratory regulation by steroids in newborn rats: a sex-specific balance between allopregnanolone and progesterone receptors

Abstract

What is the central question of this study? What are the contributions of allopregnanolone, the neuroactive metabolite of progesterone, and nuclear (nPR) and membrane (mPR) progesterone receptors to the respiratory effect of progesterone in newborn rats? What is the main finding and its importance? Acute progesterone injection increases the apnoea frequency, whereas finasteride (which blocks the conversion of progesterone to allopregnanolone) reduces apnoea frequency. An nPR agonist decreases apnoea frequency in males and an mPR agonist decreases apnoea frequency in males and females. Chronic injection of progesterone decreases the frequency of apnoea more efficiently in males than in females. We tested the hypothesis that the effects of progesterone on apnoea frequency in newborn rats are the result of a balance between its neuroactive metabolite, allopregnanolone (GABA_A receptor modulator), and progesterone receptors. We used male and female rats between 10 and 12 days of age and recorded respiratory and metabolic parameters (whole-body plethysmography), and assessed the frequency and duration of apnoeas in normoxia. We tested the effects of a single injection of progesterone (4 mg kg^-1 , i.p.), finasteride (10 mg kg^-1 , i.p.; a 5α-reductase antagonist, which blocks the conversion of progesterone to allopregnanolone), finasteride plus progesterone, or agonists of the nuclear or membrane progesterone receptors (R5020 or Org-od-02-0, 4 mg kg^-1 ). To test the hypothesis that chronic exposure to progesterone reduces the frequency of apnoeas, we used male and female rats treated daily with progesterone between postnatal days 3 and 12. The acute injection of progesterone reduced minute ventilation and metabolic rate and increased the frequency of apnoeas. Finasteride decreased the frequency of apnoeas, and finasteride plus progesterone did not increase apnoea frequency but decreased minute ventilation in female rats. Although R5020 decreased apnoea frequency only in males, Org-od-02-0 decreased apnoea frequency in males and females and decreased respiratory frequency in females. Chronic progesterone treatment reduced apnoea frequency more efficiently in males than in females, but in females (not in males) an acute injection of caffeine (the gold standard for the treatment of apnoea in preterm neonates) further reduced apnoea frequency. Apnoea frequency in newborn rats is, in part, determined by a sex-specific balance between allopregnanolone, GABA_A receptors and progesterone receptors.

Keywords: allopregnanolone; apnoea; caffeine; neurosteroid; newborn rats; progesterone; ventilation.