The relation between changes in brain and plasma concentrations of neurosteroids and the function and structure of ␥-aminobutyric acid type A (GABA A ) receptors in the brain during pregnancy and after delivery was investigated in rats. In contrast with plasma, where all steroids increased in parallel, the kinetics of changes in the cerebrocortical concentrations of progesterone, allopregnanolone (AP), and allotetrahydrodeoxycorticosterone (THDOC) diverged during pregnancy. Progesterone was already maximally increased between days 10 and 15, whereas AP and allotetrahydrodeoxycorticosterone peaked around day 19. The stimulatory effect of muscimol on 36 Cl ؊ uptake by cerebrocortical membrane vesicles was decreased on days 15 and 19 of pregnancy and increased 2 days after delivery. Moreover, the expression in cerebral cortex and hippocampus of the mRNA encoding for ␥2L GABA A receptor subunit decreased during pregnancy and had returned to control values 2 days after delivery. Also ␣1,␣2, ␣3, ␣4, ␤1, ␤2, ␤3, and ␥2S mRNAs were measured and failed to change during pregnancy. Subchronic administration of finasteride, a 5␣-reductase inhibitor, to pregnant rats reduced the concentrations of AP more in brain than in plasma as well as prevented the decreases in both the stimulatory effect of muscimol on 36 Cl ؊ uptake and the decrease of ␥2L mRNA observed during pregnancy. These results indicate that the plasticity of GABA A receptors during pregnancy and after delivery is functionally related to f luctuations in endogenous brain concentrations of AP whose rate of synthesis͞metabolism appears to differ in the brain, compared with plasma, in pregnant rats.An important feature of ␥-aminobutyric acid type A (GABA A ) receptors in rat brain is their plasticity in response to exposure to brief or long-lasting physiological stimuli or to long-term pharmacological treatments. The kinetic characteristics of the various binding sites located on the GABA A receptor, as well as the density and function of these receptors in different areas of the rat brain, are affected by acute stressful stimuli (handling, foot shock, swimming), postnatal development, aging, kindling, and long-term administration of anxiolytic, hypnotic, or anticonvulsant drugs (1-6). Although recent studies have suggested that some of these changes may be mediated at the level of expression of receptor subunit genes (7-10), the chemical or molecular events that underlie such rapid, shortterm, or persistent changes in the density and affinity of binding sites associated with GABA A receptors, as well as in the function of the receptor complex, remain to be characterized.Neurosteroids accumulate in the mammalian brain in a manner that is, at least in part, independent of the peripheral tissues (adrenal glands and gonads) that synthesize these compounds (11). Systemic administration of progesterone or its metabolites 3␣-hydroxy-5␣-pregnan-20-one (allopregnanolone, AP) and 3␣,21-dihydroxy-5␣-pregnan-20-one (allotetrahydrodeoxycorticosterone, THDOC) induces an...

Abstract:The effects of social isolation on behavior, neuroactive steroid concentrations, and GABA A receptor function were investigated in rats. Animals isolated for 30 days immediately after weaning exhibited an anxiety-like behavioral profile in the elevated plus-maze and Vogel conflict tests. This behavior was associated with marked decreases in the cerebrocortical, hippocampal, and plasma concentrations of pregnenolone, progesterone, allopregnanolone, and allotetrahydrodeoxycorticosterone compared with those apparent for group-housed rats; in contrast, the plasma concentration of corticosterone was increased in the isolated animals. Acute footshock stress induced greater percentage increases in the cortical concentrations of neuroactive steroids in isolated rats than in group-housed rats. Social isolation also reduced brain GABA A receptor function, as evaluated by measuring both GABA-evoked Cl Ϫ currents in Xenopus oocytes expressing the rat receptors and tert-[ 35 S]butylbicyclophosphorothionate ([ 35 S]TBPS) binding to rat brain membranes. Whereas the amplitude of GABAinduced Cl Ϫ currents did not differ significantly between group-housed and isolated animals, the potentiation of these currents by diazepam was reduced at cortical or hippocampal GABA A receptors from isolated rats compared with that apparent at receptors from group-housed animals. Moreover, the inhibitory effect of ethyl-␤-carboline-3-carboxylate, a negative allosteric modulator of GABA A receptors, on these currents was greater at cortical GABA A receptors from socially isolated animals than at those from group-housed rats. Finally, social isolation increased the extent of [ 35 S]TBPS binding to both cortical and hippocampal membranes. The results further suggest a psychological role for neurosteroids and GABA A receptors in the modulation of emotional behavior and mood.

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The time courses of changes in rat brain neuroactive steroid concentrations and γ-aminobutyric acid type A (GABA_A) receptor function elicited by acute stress were investigated in animals exposed to CO₂ for 1 min, a treatment known to induce stress in rats and panic attacks in humans. Inhalation of CO₂ induced increases in cerebral cortical steroid concentrations, the time dependence of which varied with the steroid examined. Thus, progesterone and deoxycorticosterone showed maximal increases (10- and 4-fold, respectively) 10 min after CO₂ inhalation and had returned to basal values by 30 and 60 min, respectively. In contrast, pregnenolone and 3_α-hydroxy-5_α-pregnan-20-one (allopregnanolone) concentrations showed maximal increases (+174 and +200%, respectively) at 30 min, were still higher than control at 60 min and returned to control values 120 min after stress. Inhalation of CO₂ also resulted in increases in plasma steroid concentrations, most of which peaked at 30 min and had returned to control values by 60 min. A parallel analysis of the stress-induced changes in GABA_A receptor function, assessed either biochemically by t-[³⁵S]butylbicyclophosphorothionate ([³⁵S]TBPS) binding to cerebral cortical membranes or behaviorally by the punished responding score in Vogel’s test, showed that the effects of CO₂ inhalation on both parameters were maximal (+51 and –40%, respectively) after 10 min; the behavioral reaction returned to normal after 60 min, whereas [³⁵S]TBPS binding had returned to control values 120 min after stress. The results show that: (a) the maximal increase in the brain concentrations of allopregnanolone, a potent and efficacious positive modulator of GABA_A receptors, occurred at a time (30 min) when both conflict behavior and [³⁵S]TBPS binding begun to decrease, and (b) both allopregnanolone concentrations and [³⁵S]TBPS binding had returned to control values 120 min after CO₂ inhalation. The data are thus consistent with a physiological role of neuroactive steroids in restoring GABAergic tone after stress.

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