FUNCTIONAL CORRELATION BETWEEN ALLOPREGNANOLONE AND [S-35] TBPS BINDING IN THE BRAIN OF RATS EXPOSED TO ISONIAZID, PENTYLENETETRAZOL OR STRESS

1 The relation between changes in the cerebral cortical concentration of allopregnanolone and gamma-aminobutyric acid (GABA) type A receptor function after intracerebroventricular injection of this neurosteroid was investigated in male rats. 2 Intracerebroventricular administrati on of allopregnanolone (1.25 to 15 mu g) produced a maximal increase ( 100 fold at the highest dose) in cortical allopregnanolone concentrati on within 5 min; the concentration remained significantly increased at 15 and 30 min, before returning to control values by 60 min. 3 The sa me treatment induced a rapid and dose-dependent decrease in the bindin g of t-[S-35]-butylbicyclophosphorothionate ([S-35]-TBPS) to cerebral cortical membranes measured ex vivo, an effect mimicked by the benzodi azepine midazolam but not by the 3 beta-hydroxyepimer of allopregnanol one. The time course of changes in [S-35]-TBPS binding paralleled that of brain allopregnanolone concentration. 4 In a dose-dependent manner , allopregnanolone both delayed the onset of convulsions and inhibited the increase in [S-35]-TBPS binding to cortical membranes induced by isoniazid. The potency of allopregnanolone in inhibiting [S-35]-TBPS b inding in isoniazid-treated rats was approximately four times that in control animals. 5 The ability of allopregnanolone to decrease [S-35]- TBPS binding in isoniazid-treated rats also correlated with its antico nvulsant activity against pentylenetetrazol-induced seizures as well a s its inhibitory effect on the increase in [S-35]-TBPS binding induced by foot shock. 6 The results indicate that the in vivo administration of allopregnanolone enhances the function of GABA(A) receptors in rat cerebral cortex and antagonizes the inhibitory action of stress and d rugs that reduce GABAergic transmission.