title: Estradiol and testosterone modulate the anesthetic action of the GABA-A agonist THIP, but not of the neurosteroid 3alpha,5beta-pregnanolone in the rat.
abstract: 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.
authors.affiliation: Centro de Investigación en Reproducción Animal, CINVESTAV-Universidad Autónoma de Tlaxcala, Apdo Postal 62 Tlaxcala, 90 000 Tlaxcala, México. oglezflo@prodigy.net.mx
authors.forename: Oscar
authors.initials: O
authors.lastname: González-Flores
authors.forename: Norma
authors.initials: N
authors.lastname: Sánchez
authors.forename: Marcos
authors.initials: M
authors.lastname: García-Juárez
authors.forename: Francisco Javier
authors.initials: FJ
authors.lastname: Lima-Hernández
authors.forename: Gabriela
authors.initials: G
authors.lastname: González-Mariscal
authors.forename: Carlos
authors.initials: C
authors.lastname: Beyer
mesh_terms: 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*
chemical_list: D000777:Anesthetics; D018755:GABA Agonists; D007555:Isoxazoles; D011963:Receptors, GABA-A; D013739:Testosterone; D004958:Estradiol; D011280:Pregnanolone; C015542:gaboxadol