GENETIC-DIFFERENCES IN BEHAVIORAL SENSITIVITY TO A NEUROACTIVE STEROID

Recent work found that lower endogenous levels of the gamma-aminobutyr ic acid-agonist, neuroactive steroid 3 alpha-hydroxy-5 alpha-pregnan-2 0-one (3 alpha,5 alpha-THP) may be correlated with increased ethanol w ithdrawal severity in the selectively bred Withdrawal Seizure-Prone an d -Resistant mice. The present studies were conducted to determine whe ther decreased sensitivity to 3 alpha,5 alpha-THP was correlated with ethanol withdrawal hyperexcitability in another genetic mouse model, n amely the C57BL/6 (B6) and DBA/2 (D2) inbred strains. These strains al so differ in ethanol withdrawal severity (D2 >> B6). B6 and D2 male mi ce were injected with 3 alpha,5 alpha-THP (0-10 mg/kg i.p.) 15 min bef ore the timed tail vein infusion of pentylenetetrazol. B6 mice were mo re sensitive than D2 animals to the anticonvulsant effect of 3 alpha,5 alpha-THP. Subsequent studies measured sensitivity to several of the pharmacological effects of 3 alpha,5 alpha-THP. B6 and D2 male mice we re injected with 3 alpha,5 alpha-THP (0-32 mg/kg) before testing for l ocomotor activation (total number of entries) and anxiolysis (percent open arm entries) on the elevated plus maze, muscle relaxation (impair ment of forelimb grip strength), ataxia (impairment of Rotarod perform ance) and seizure susceptibility to pentylenetetrazol. B6 mice were mo re sensitive than D2 animals to the anxiolytic, locomotor stimulant an d anticonvulsant effects of 3 alpha,5 alpha-THP. In contrast, D2 mice were more sensitive than B6 mice to 3 alpha,5 alpha-THP-induced muscle relaxation and ataxia. Plasma 3 alpha,5 alpha-THP levels did not diff er in the B6 and D2 mice injected with this steroid, suggesting that t he strain differences were not pharmacokinetic. Collectively, the resu lts in selectively bred Withdrawal Seizure-Prone and -Resistant mice a nd B6 and D2 inbred strains suggest that genetic differences in neuroa ctive steroid sensitivity and biosynthesis may contribute to ethanol w ithdrawal severity.