Vol. 280, Issue 2, 820-828, 1997

Genetic Differences in Behavioral Sensitivity to a Neuroactive Steroid

Deborah A. Finn¹, Amanda J. Roberts², Frank Lotrich and Edward J. Gallaher

Research Service, Department of Veterans Affairs Medical Center and Department of Behavioral Neuroscience, Oregon Health Sciences University, Portland, Oregon

Recent work found that lower endogenous levels of the -aminobutyric acid-agonist, neuroactive steroid 3-hydroxy-5-pregnan-20-one (3,5-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 3,5-THP was correlated with ethanol withdrawal hyperexcitability in another genetic mouse model, namely the C57BL/6 (B6) and DBA/2 (D2) inbred strains. These strains also differ in ethanol withdrawal severity (D2 B6). B6 and D2 male mice were injected with 3,5-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 3,5-THP. Subsequent studies measured sensitivity to several of the pharmacological effects of 3,5-THP. B6 and D2 male mice were injected with 3,5-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 3,5-THP. In contrast, D2 mice were more sensitive than B6 mice to 3,5-THP-induced muscle relaxation and ataxia. Plasma 3,5-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.