Steroid regulation of the GABAA receptor: ligand binding, chloride transport and behaviour

Certain endogenous steroids are modulators of GABAA receptors. Tetrahydroprogesterone (THP, 5 alpha-pregnan-3 alpha-ol-20-one) and tetrahydrodeoxy-corticosterone (THDOC, 5 alpha-pregnane-3 alpha, 21-diol-20-one) behave as allosteric agonists of GABAA receptors whereas pregnenolone sulphate acts as an antagonist. THP and THDOC modulate ligand binding to GABAA receptors like barbiturates; they potentiate binding of the GABAA receptor agonist muscimol and the benzodiazepine flunitrazepam and they allosterically inhibit binding of the convulsant t-butylbicyclophosphorothionate. THP and THDOC also stimulate chloride uptake and currents in synaptoneurosomes and neurons. Pregnenolone sulphate acts principally as an allosteric GABAA receptor antagonist; it competitively inhibits binding of [35S] TBPS and blocks GABA agonist-activated Cl- uptake and currents in synaptoneurosomes and neurons. In behavioural experiments the GABA-agonistic steroid THDOC shows anxiolytic actions whereas the GABA-antagonistic steroid pregnenolone sulphate antagonizes barbiturate-induced hypnosis. Changes in physiological levels of GABAergic steroids may alter GABAA receptor function, influencing neuronal excitability and CNS arousal. For example, pregnancy and the puerperium are associated with alterations in GABAA receptor binding which might be attributable to steroid actions.