GABAergic activation inhibits the hypothalamic-pituitary-ovaric axis and sexual development in the immature female rat. Associated changes in hypothalamic glutamatergic and taurinergic systems.
The aim of the present studies was to assess, in immature female rats, the effect of the GABAergic system on the reproductive axis and on pubertal development. With this purpose we initially evaluated, in 30-day-old female rats, the effect of persistently enhanced GABAergic activity (aminooxyacetic acid (AOAA) 10 mg/kg per day i.p., during postnatal days 23-29) on hypothalamic gonadotropin-releasing hormone (GnRH) and amino acid neurotransmitter (AANT; glutamate or GLU, and taurine or TAU) concentrations, on circulating luteinizing hormone (LH) and estradiol levels, and on ovaric weight. In a second group of similarly treated rats, the date of vaginal opening (VO) was recorded. Complementary in vitro experiments (superfusion of anterior/mediobasal hypothalamic fragments obtained from rats aged 30 days) were performed to evaluate the effect of the short-term activation of the GABAergic system (by means of AOAA, muscimol or baclofen) on hypothalamic GnRH and AANT release. Prolonged treatment with AOAA led to a marked increase in hypothalamic gamma-aminobutyric-acid (GABA) concentrations (p<0.002), and to a significant decrease in hypothalamic GnRH and GLU content (p<0.05 and <0.02, respectively). Furthermore, treated animals showed diminished serum LH (p<0.05) and estradiol (p<0.005) levels, and a clear reduction in ovaric weight (p<0.002). Mean age at VO was 30. 8+/-0.6 days in control animals (range: 29-34 days), and 36.7+/-0.98 days in AOAA-treated rats (range: 33-40 days; p<0.0001). Acute treatment with AOAA resulted in a decreased GnRH and GLU output, and in an increased TAU release from superfused hypothalamic fragments. This effect was mimicked by the GABA-A and GABA-B agonists. Our results show that the activation of the GABAergic system during postnatal days 23-29 significantly restrains the hypothalamic-pituitary-ovaric axis, resulting in a clear-cut delay in sexual development. This can be attributed to the inhibitory effect exerted by GABA (acting on both GABA-A and GABA-B receptor subtypes) on GnRH release. Furthermore, the pharmacologic manipulation of the GABAergic system induces significant changes in the release of GLU and TAU, giving biochemical support to the existence of a physiological cross-talk between the excitatory and inhibitory AANT regulating GnRH release during the onset of puberty.
Feleder
C
C
Departamento de Fisiología, Facultad de Medicina, Universidad de Buenos Aires, Paraguay 2155, (1121), Buenos Aires, Argentina.
Ginzburg
M
M
Wuttke
W
W
Moguilevsky
J A
JA
Arias
P
P
D000625:Aminooxyacetic Acid / Q000494:pharmacology; D000818:Animals; D001418:Baclofen / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004958:Estradiol / Q000097:blood; D005260:Female; D018755:GABA Agonists / Q000494:pharmacology; D018698:Glutamic Acid / Q000502:physiology*; D007030:Hypothalamo-Hypophyseal System / Q000502:physiology*; D007986:Luteinizing Hormone / Q000097:blood; D009118:Muscimol / Q000494:pharmacology; D009929:Organ Size; D010053:Ovary / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D012741:Sexual Maturation / Q000502:physiology*; D013654:Taurine / Q000502:physiology*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism / Q000502:physiology*
D004791:Enzyme Inhibitors; D018755:GABA Agonists; D000625:Aminooxyacetic Acid; D013654:Taurine; D009118:Muscimol; D018698:Glutamic Acid; D004958:Estradiol; D005680:gamma-Aminobutyric Acid; D007986:Luteinizing Hormone; D001418:Baclofen