title: Antiandrogen microimplants into the rostral medial preoptic area decrease gamma-aminobutyric acidergic neuronal activity and increase luteinizing hormone secretion in the intact male rat.
abstract: gamma-Aminobutyric acid (GABA)ergic neurons terminating in the rostral hypothalamus are stimulated by testosterone. To investigate whether this action is mediated locally through androgen receptors in the rostral hypothalamus, bilateral microcannulas (28 gauge) containing the androgen receptor antagonist, hydroxyflutamide (HF), were stereotaxically implanted into the rostral medial preoptic area (rMPA) just dorsal to the major population of GnRH cell bodies. Two days later, blood samples were collected for assay of LH, and animals were killed for determination of GABAergic neuronal activity in tissue dissected from the site of the implanted cannulas. Animals were decapitated either without treatment or 60 min after inhibition of GABA degradation by aminooxyacetic acid (100 mg/kg, ip). The rate of GABA accumulation in the tissue after aminooxyacetic acid treatment was used as a measure of GABA turnover. Levels of messenger RNA for both forms of glutamic acid decarboxylase (GAD65 and GAD67), the rate-limiting enzyme responsible for GABA synthesis also were measured by a microlysate ribonuclease protection assay. LH levels were significantly increased (1.8-fold) in HF-treated animals compared with controls. In the MPA, beneath the implant cannulas, GABA turnover was significantly reduced in HF-treated rats. There was no effect of treatment in the frontal cortex, which was used as a control region. Surprisingly, levels of messenger RNA for both GAD65 and GAD67 were significantly increased in HF-treated rats. The results indicate that GABAergic neurons terminating in the rostral hypothalamus are tonically stimulated by testosterone acting by means of androgen receptors localized in this region. These findings support the working hypothesis that androgen-sensitive GABAergic neurons in the rMPA mediate the negative feedback action of testosterone on GnRH secretion in the male rat.
authors.affiliation: Department of Physiology, University of Maryland School of Medicine, Baltimore 21201-1559, USA.
authors.forename: D R
authors.initials: DR
authors.lastname: Grattan
authors.forename: M S
authors.initials: MS
authors.lastname: Rocca
authors.forename: C A
authors.initials: CA
authors.lastname: Sagrillo
authors.forename: M M
authors.initials: MM
authors.lastname: McCarthy
authors.forename: M
authors.initials: M
authors.lastname: Selmanoff
mesh_terms: D000726:Androgen Antagonists / Q000008:administration & dosage* / Q000494:pharmacology; D000818:Animals; D004343:Drug Implants; D005485:Flutamide / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D005968:Glutamate Decarboxylase / Q000235:genetics; D007527:Isoenzymes / Q000235:genetics; D007986:Luteinizing Hormone / Q000097:blood / Q000378:metabolism*; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D011301:Preoptic Area / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013739:Testosterone / Q000037:antagonists & inhibitors / Q000502:physiology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism / Q000502:physiology*
chemical_list: D000726:Androgen Antagonists; D004343:Drug Implants; D007527:Isoenzymes; D012333:RNA, Messenger; C014290:hydroxyflutamide; D013739:Testosterone; D005680:gamma-Aminobutyric Acid; D005485:Flutamide; D007986:Luteinizing Hormone; D005968:Glutamate Decarboxylase