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Estradiol and testosterone modulate the anesthetic action of the GABA-A agonist THIP, but not of the neurosteroid 3α,5β-pregnanolone in the rat

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Abstract

Rationale

As sex steroids modify the number and distribution of brain γ-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.

Objectives

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: 3α-hydroxy-5β-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 μg/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.

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  1. Centro de Investigación en Reproducción Animal, CINVESTAV-Universidad Autónoma de Tlaxcala, Apdo. Postal 62. Tlaxcala, 90 000, Tlaxcala, México

    Oscar González-Flores, Norma Sánchez, Marcos García-Juárez, Francisco Javier Lima-Hernández, Gabriela González-Mariscal & Carlos Beyer

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  1. Oscar González-Flores
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  2. Norma Sánchez
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  3. Marcos García-Juárez
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  4. Francisco Javier Lima-Hernández
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  5. Gabriela González-Mariscal
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  6. Carlos Beyer
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Correspondence to Oscar González-Flores.

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González-Flores, O., Sánchez, N., García-Juárez, M. et al. Estradiol and testosterone modulate the anesthetic action of the GABA-A agonist THIP, but not of the neurosteroid 3α,5β-pregnanolone in the rat. Psychopharmacology 172, 283–290 (2004). https://doi.org/10.1007/s00213-003-1649-x

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