Allopregnanolone acts as an inhibitory modulator on α₁- and α₆-containing GABA_A receptors

Allopregnanolone, known so far to act as a γ-aminobutyric acid (GABA) agonist, allosterically decreased the affinity of the GABA agonist muscimol for recombinant α₁β_2γ2 and α₆β_2γ2 GABA_A receptors. Pregnenolone sulfate, a GABA antagonist, had a similar effect. Both of these neuroactive steroids also reduced the time constant of desensitization (τ) of GABA-induced chloride currents. The effect on desensitization was demonstrated for native receptors of hypothalamic neurons as well as for the recombinant GABA_A receptors. Hence neuroactive steroids may differentially modulate distinct assemblies of GABA_A receptors and thus induce a more subtle modulation of GABAergic synaptic transmission than previously thought possible.