TIME-DEPENDENT CHANGES IN RAT-BRAIN NEUROACTIVE STEROID CONCENTRATIONS AND GABA(A) RECEPTOR FUNCTION AFTER ACUTE STRESS

The time courses of changes in rat brain neuroactive steroid concentra tions and gamma-aminobutyric acid type A (GABA(A)) receptor function e licited by acute stress were investigated in animals exposed to CO2 fo r 1 min, a treatment known to induce stress in rats and panic attacks in humans. Inhalation of CO2 induced increases in cerebral cortical st eroid concentrations, the time dependence of which varied with the ste roid examined. Thus, progesterone and deoxycorticosterone showed maxim al increases (10- and 4-fold, respectively) 10 min after CO2 inhalatio n and had returned to basal values by 30 and 60 min, respectively. In contrast, pregnenolone and 3 alpha-hydroxy-5 alpha-pregnan-20-one (all opregnanolone) concentrations showed maximal increases (+174 and +200% , respectively) at 30 min, were still higher than control at 60 min an d returned to control values 120 min after stress. Inhalation of CO2 a lso resulted in increases in plasma steroid concentrations, most of wh ich peaked at 30 min and had returned to control values by 60 min. A p arallel analysis of the stress-induced changes in GABA(A) receptor fun ction, assessed either biochemically by t-[S-35]butylbicyclophosphorot hionate ([S-35]TBPS) binding to cerebral cortical membranes or behavio rally by the punished responding score in Vogel's test, showed that th e effects of CO2 inhalation on both parameters were maximal(+51 and -4 0%, respectively) after 10 min; the behavioral reaction returned to no rmal after 60 min, whereas [S-35]TBPS binding had returned to control values 120 min after stress. The results show that: (a) the maximal in crease in the brain concentrations of allopregnanolone, a potent and e fficacious positive modulator of GABA(A) receptors, occurred at a time (30 min) when both conflict behavior and [S-35]TBPS binding begun to decrease, and (b) both allopregnanolone concentrations and [S-35]TBPS binding had returned to control values 120 min after CO2 inhalation. T he data are thus consistent with a physiological role of neuroactive s teroids in restoring GABAergic tone after stress.