Long-term social isolation enhances picrotoxin seizure susceptibility in mice: up-regulatory role of endogenous brain allopregnanolone in GABAergic systems

Allopregnanolone (ALLO, 3alpha,5alpha-tetrahydroprogesterone), a positive allosteric modulator of actions of gamma-aminobutyric acid GABA) at GABA(A) receptors, is synthesized in the brain from progesterone by the sequential action of two enzymes: a type I 5alpha-reductase and a 3alpha-hydroxysteroid oxidoreductase. We previously demonstrated that long-term social isolation of mice caused a significant decrease in brain ALLO content via suppression of type I 5alpha-reductase and its mRNA expression. In this study, to clarify a physiological role of endogenous brain ALLO, we investigated changes in seizure susceptibility of mice following protracted social isolation and compared with those of mice treated with SKF 105111 (SKF), an inhibitor of types I and II 5alpha-reductase. Social isolation of mice for 7 weeks prior to the experiments caused a significant increase of seizure susceptibility to the GABA(A) receptor antagonist picrotoxin but not to the glycine receptor antagonist strychnine or the glutamate receptor agonist kainic acid. The change in the seizure susceptibility was completely reversed by 2.5 mg/kg ip ALLO, a dose that per se had no effect on picrotoxin-induced seizure. Treatment of mice with SKF (20 mg/kg ip) also reduced a threshold dose of picrotoxin, but not that of strychnine or kainic acid, which was required to elicit seizure in group-housed mice. The effect of SKF was attenuated by ALLO (2.5 mg/kg ip). In contrast, SKF treatment had no effect on picrotoxin-induced seizure in socially isolated mice. These findings suggest that endogenous brain ALLO plays a suppressive role in seizure susceptibility via a positive modulation of GABA(A) receptor function and that social isolation enhances seizure susceptibility in mice via reduction of GABA(A) receptor function caused by a decrease of endogenous ALLO. (C) 2003 Elsevier Inc. All rights reserved.