Genetic differences in behavioral sensitivity to a neuroactive steroid

Recent work found that lower endogenous levels of the γ-aminobutyric acid-agonist, neuroactive steroid 3α-hydroxy-5α-pregnan-20-one (3α,5α- THP) may be correlated with increased ethanol withdrawal severity in the selectively bred Withdrawal Seizure-Prone and -Resistant mice. The present studies were conducted to determine whether decreased sensitivity to 3α,5α- THP was correlated with ethanol withdrawal hyperexcitability in another genetic mouse model, namely the C57BL/6 (B6) and DBN2 (D2) inbred strains. These strains also differ in ethanol withdrawal severity (D2 >> B6). B6 and D2 male mice were injected with 3α,5α-THP (0-10 mg/kg i.p.) 15 min before the timed tail vein infusion of pentylenetetrazol. B6 mice were more sensitive than D2 animals to the anticonvulsant effect of 3α,5α-THP. Subsequent studies measured sensitivity to several of the pharmacological effects of 3α,5α-THP. B6 and D2 male mice were injected with 3α,5α-THP (0-32 mg/kg) before testing for locomotor activation (total number of entries) and anxiolysis (percent open arm entries) on the elevated plus maze, muscle relaxation (impairment of forelimb grip strength), ataxia (impairment of Rotarod performance) and seizure susceptibility to pentylenetetrazol. B6 mice were more sensitive than D2 animals to the anxiolytic, locomotor stimulant and anticonvulsant effects of 3α,5α-THP. In contrast, D2 mice were more sensitive than B6 mice to 3α,5α-THP-induced muscle relaxation and ataxia. Plasma 3α,5α-THP levels did not differ in the B6 and D2 mice injected with this steroid, suggesting that the strain differences were not pharmacokinetic. Collectively, the results in selectively bred Withdrawal Seizure-Prone and -Resistant mice and B6 and D2 inbred strains suggest that genetic differences in neuroactive steroid sensitivity and biosynthesis may contribute to ethanol withdrawal severity.