Neurosteroids as Endogenous Regulators of Seizure Suscepibility.

Abstract

Stress-induced Deoxycorticosterone-derived Neurosteroids Modulate GABAA Receptor Function and Seizure Susceptibility Reddy DS, Rogawski MA J Neurosci 2002;22:3795–3805 Stress affects seizure susceptibility in animals and humans, but the underlying mechanisms are obscure. Here we provide evidence that γ-aminobutyric acid subunit A (GABAA) receptor-modulating neurosteroids derived from deoxycorticosterone (DOC) play a role in stress-related changes in seizure control. DOC, an adrenal steroid, the synthesis of which is enhanced during stress, undergoes sequential metabolic reduction by 5α-reductase and 3α-hydroxysteroid oxidoreductase to form 5α-dihydrode-oxycorticosterone (DHDOC) and allotetrahydrodeoxycorti-costerone (THDOC), a GABAA receptor-modulating neurosteroid with anticonvulsant properties. Acute swim stress in rats significantly elevated plasma THDOC concentrations and raised the pentylenetetrazol (PTZ) seizure threshold. Small systemic doses of DOC produced comparable increases in THDOC and PTZ seizure thresholds. Pretreatment with finasteride, a 5α-reductase inhibitor that blocks the conversion of DOC to DHDOC, reversed the antiseizure effects of stress. DOC also elevated plasma THDOC levels and protected mice against PTZ, methyl-6,7-dimethoxy-4-ethyl-β-carboline-3-carboxylate, picrotoxin, and amygdala-kindled seizures in mice (ED50 values, 84–97 mg/kg). Finasteride reversed the antiseizure activity of DOC (ED50, 7.2 mg/kg); partial antagonism also was obtained with indomethacin (100 mg/kg), an inhibitor of 3α-hydroxysteroid oxidoreductase. Finasteride had no effect on seizure protection by DHDOC and THDOC, whereas indomethacin partially reversed DHDOC but not THDOC. DHDOC, like THDOC, potentiated GABA-activated Cl– currents in cultured hippocampal neurons (≤1 μ) and directly activated GABAA receptor currents (≤1 μ M), compatible with a role for DHDOC in the antiseizure activity of DOC. DOC is a mediator of the physiological effects of acute stress that could contribute to stress-induced changes in seizure susceptibility through its conversion to neurosteroids with modulatory actions on GABAA receptors including THDOC and possibly also DHDOC. Enhanced Neurosteroid Potentiation of Ternary GABAA Receptors Containing the δ Subunit Wohlfarth KM, Bianchi MT, Macdonald RL J Neurosci 2002;22:1541–1549 Attenuated behavioral sensitivity to neurosteroids has been reported for mice deficient in the γ-aminobutyric acid subunit A [GABA(A)]-receptor δ subunit. We therefore investigated potential subunit-specific neurosteroid pharmacology of the following GABAA-receptor isoforms in a transient expression system: α1β372L, α1β38, α6β372L, and α6β38. Potentiation of submaximal GABAA-receptor currents by the neurosteroid tetrahydrodeoxycorticosterone (THDOC) was greatest for the α1β38 isoform. Whole-cell GABA concentration-response curves performed with and without low concentrations (30 n M) of THDOC revealed enhanced peak GABAA-receptor currents for isoforms tested without affecting the GABA EC50. The α1β38 currents were enhanced the most (>150%), whereas the other isoform currents were enhanced 15–50%. At a higher concentration (1 μ M), THDOC decreased peak α1β382L-receptor current amplitude evoked by GABA (1 m M) concentration jumps and prolonged deactivation but had little effect on the rate or extent of apparent desensitization. Thus the polarity of THDOC modulation depended on GABA concentration for α1β382L GABAA receptors. However, the same protocol applied to α1β38 receptors resulted in peak current enhancement by THDOC of >800% and prolonged deactivation. Interestingly, THDOC induced pronounced desensitization in the minimally desensitizing α1β38 receptors. Single-channel recordings obtained from α1β38 receptors indicated that THDOC increased the channel-opening duration, including the introduction of an additional longer duration open state. Our results suggest that the GABAA-receptor delta subunit confers increased sensitivity to neurosteroid modulation and that the intrinsic gating and desensitization kinetics of α1β38 GABAA receptors are altered by THDOC.