Increased behavioral neurosteroid sensitivity in a rat line selectively bred for high alcohol sensitivity.
Acute administration of a neurosteroid 5beta-pregnan-3alpha-ol-20-one induced a greater impairment in motor performance of the selectively bred alcohol-sensitive (ANT) than alcohol-insensitive (AT) rats. This difference was not associated with the sensitivity of gamma-aminobutyrate type A (GABA(A)) receptors, as 5alpha-pregnan-3alpha-ol-20-one (allopregnanolone) decreased the autoradiographic signals of t-butylbicyclophosphoro[35S]thionate binding to GABA(A) receptor-associated ionophores more in the brain sections of AT than ANT rats. Nor was the difference associated with baseline levels of neuroactive progesterone metabolites, as 5alpha-pregnan-3,20-dione (5alpha-DHP) and 5alpha-pregnan-3alpha-ol-20-one were lower in the ANT rats. After ethanol (2 g/kg, i.p.) administration and the subsequent motor performance test, the increased brain concentrations of these metabolites were still lower in the ANT than AT rats, although especially in the cerebellum the relative increases were greater in the ANT than AT rats. The present data suggest that the mechanisms mediating neurosteroid-induced motor impairment are susceptible to genetic variation in rat lines selected for differences in ethanol intoxication.
Korpi
E R
ER
Department of Pharmacology and Clinical Pharmacology, University of Turku, FIN-20520, Turku, Finland. eas.korpi@utu.fi
Mäkelä
R
R
Romeo
E
E
Guidotti
A
A
Uusi-Oukari
M
M
Furnari
C
C
di Michele
F
F
Sarviharju
M
M
Xu
M
M
Rosenberg
P H
PH
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D001947:Breeding; D004305:Dose-Response Relationship, Drug; D000431:Ethanol / Q000494:pharmacology*; D005260:Female; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D011280:Pregnanolone / Q000031:analogs & derivatives / Q000494:pharmacology*; D051381:Rats; D011963:Receptors, GABA-A / Q000187:drug effects / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
D011963:Receptors, GABA-A; D000431:Ethanol; C028952:allopregnan-20 alpha-ol-3-one; D005680:gamma-Aminobutyric Acid; D011280:Pregnanolone