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Genetic differences in behavioral sensitivity to a neuroactive steroid

D A Finn1, A J Roberts, F Lotrich

  • 1Research Service, Department of Veterans Affairs Medical Center, Portland, Oregon 97201, USA.

The Journal of Pharmacology and Experimental Therapeutics
|February 1, 1997
PubMed
Summary
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Genetic differences in sensitivity to the neuroactive steroid 3alpha,5alpha-THP influence ethanol withdrawal severity. Mouse strains with lower sensitivity showed increased withdrawal hyperexcitability, suggesting a link between steroid biosynthesis and withdrawal symptoms.

Area of Science:

  • Neuroscience
  • Pharmacology
  • Genetics

Background:

  • Lower endogenous levels of the neuroactive steroid 3alpha-hydroxy-5alpha-pregnan-20-one (3alpha,5alpha-THP), a gamma-aminobutyric acid-agonist, are potentially linked to increased ethanol withdrawal severity.
  • Previous studies identified correlations in selectively bred mouse lines, but this research investigates genetic differences in inbred strains.

Purpose of the Study:

  • To determine if decreased sensitivity to 3alpha,5alpha-THP correlates with ethanol withdrawal hyperexcitability in C57BL/6 (B6) and DBA/2 (D2) inbred mouse strains.
  • To compare the sensitivity of B6 and D2 mice to various pharmacological effects of 3alpha,5alpha-THP.

Main Methods:

  • Mice (B6 and D2 males) were administered varying doses of 3alpha,5alpha-THP before testing for anticonvulsant effects against pentylenetetrazol-induced seizures.

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  • Subsequent studies assessed sensitivity to locomotor activation, anxiolysis (elevated plus maze), muscle relaxation (grip strength), and ataxia (Rotarod performance).
  • Plasma 3alpha,5alpha-THP levels were measured to rule out pharmacokinetic differences.

    • Main Results:

    • B6 mice exhibited greater sensitivity to the anticonvulsant, anxiolytic, and locomotor stimulant effects of 3alpha,5alpha-THP compared to D2 mice.
    • Conversely, D2 mice showed higher sensitivity to 3alpha,5alpha-THP-induced muscle relaxation and ataxia.
    • No significant differences in plasma 3alpha,5alpha-THP levels were observed between strains, indicating that observed differences were likely due to sensitivity, not pharmacokinetics.

    Conclusions:

    • Genetic variations in sensitivity to the neuroactive steroid 3alpha,5alpha-THP contribute to differing ethanol withdrawal severity between mouse strains.
    • These findings, consistent with studies in selectively bred mice, suggest that neurosteroid system alterations play a role in the genetic basis of alcohol withdrawal.