Estradiol and testosterone modulate the anesthetic action of the GABA-A agonist THIP, but not of the neurosteroid 3alpha,5beta-pregnanolone in the rat.
BACKGROUND
As sex steroids modify the number and distribution of brain gamma-aminobutyric acid (GABA)A receptor subunits, we investigated the potential modulation of anesthesia, induced by agents acting on the GABAA receptor, by estrogen and androgen.


OBJECTIVE
To assess possible effects of sex and hormonal condition (i.e., intact vs castrate; estradiol vs testosterone treatment) on the anesthetic effect of a GABAA agonist, THIP (4,5,6,7-tetrahydroisoxazolo[5,4,-c]pyridin-3-ol hydrochloride), and an allosteric modulator of the GABAA receptor: 3alpha-hydroxy-5beta-pregnan-20-one (epipregnanolone).


METHODS
The potencies of THIP and epipregnanolone for inducing loss of the righting response were compared between: (a) female and male rats; (b) intact and castrated animals of each sex; (c) untreated castrates and castrates given estradiol or testosterone.


RESULTS
Sex and endocrine condition influenced sensitivity to i.v. THIP for the induction of anesthesia. ED50 values were: gonadectomized females, 80 mg/kg>intact males, 50 mg/kg>proestrous females, 35 mg/kg>gonadectomized males, 28 mg/kg. Estradiol benzoate (EB; 3 microg/day for 5 days) significantly increased THIP sensitivity in gonadectomized females: THIP+EB: ED50=26 mg/kg vs THIP+sesame oil: ED50=94 mg/kg, while testosterone propionate (TP; 10 mg injected 24 h before THIP) decreased THIP sensitivity in orchidectomized males when compared with vehicle-injected animals (ED50=72 mg/kg vs 22 mg/kg, respectively).


CONCLUSIONS
Results suggest that estrogen increases the density or availability of GABAA receptor subtypes on which THIP acts, while testosterone exerts the opposite effect. Neither sex nor gonadal condition influenced the anesthetic action of epipregnanolone as a similar potency was found in intact and in gonadectomized males and females.
González-Flores
Oscar
O
Centro de Investigación en Reproducción Animal, CINVESTAV-Universidad Autónoma de Tlaxcala, Apdo Postal 62 Tlaxcala, 90 000 Tlaxcala, México. oglezflo@prodigy.net.mx
Sánchez
Norma
N
García-Juárez
Marcos
M
Lima-Hernández
Francisco Javier
FJ
González-Mariscal
Gabriela
G
Beyer
Carlos
C
D000758:Anesthesia; D000777:Anesthetics; D000818:Animals; D004347:Drug Interactions; D004958:Estradiol / Q000494:pharmacology*; D005260:Female; D018755:GABA Agonists / Q000494:pharmacology*; D007555:Isoxazoles / Q000494:pharmacology*; D008297:Male; D011280:Pregnanolone; D051381:Rats; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000187:drug effects; D012018:Reflex / Q000187:drug effects; D012727:Sex Characteristics; D013739:Testosterone / Q000494:pharmacology*
D000777:Anesthetics; D018755:GABA Agonists; D007555:Isoxazoles; D011963:Receptors, GABA-A; D013739:Testosterone; D004958:Estradiol; D011280:Pregnanolone; C015542:gaboxadol