Regulation of proopiomelanocortin gene expression by endogenous ligands of the GABAA receptor complex as evaluated by in situ hybridization in the rat pars intermedia.
The neurotransmitter gamma-aminobutyric acid (GABA) exerts a tonic inhibitory influence on proopiomelanocortin (POMC) neurons in the hypothalamus as well as on the melanotrope cells of the intermediate lobe (IL) of the pituitary gland. Moreover, the activation of the GABAA receptor complex by different ligands has been shown to exert a negative influence on the POMC gene expression at the hypothalamic level. In order to elucidate the in vivo regulation of the POMC mRNA levels in the intermediate lobe of the pituitary by endogenous ligands of the GABAA receptor complex, we have studied the effect of intravenous (i.v.) and intracerebroventricular (i.c.v) injections of octadecaneuropeptide (ODN), a peptide derived from diazepam-binding inhibitor (DBI). The possible involvement of neurosteroids in the action of ODN on melanotropic cells was evaluated following inhibition of two enzymes involved in the biosynthesis of neurosteroids known as activators of G3BAA receptor complex: trilostane, an inhibitor of 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD), and MK-906, an inhibitor of 5 alpha-reductase. The i.v. injection of ODN produced a dose-dependent inhibition of POMC gene expression in the IL. The i.c.v. injection of ODN also depressed POMC mRNA. These effects were completely reversed by the concomitant administration of the GABAA antagonist picrotoxin. Similar results were obtained in POMC neurons in the arcuate nucleus (AN) of the hypothalamus. Trilostane administration induced an increase in POMC mRNA and also prevented the inhibitory influence of ODN. The neurosteroid pregnenolone-sulfate, a negative modulator of the GABAA receptor, also stimulated POMC gene expression. On the other hand, MK-906 produced a decrease in mRNA levels and could not reverse the effect of ODN. The results indicate that activation of the GABAA receptor complex by the endogenous benzodiazepine receptor ligand ODN can induce a negative regulation of POMC gene expression in the IL of the pituitary and neurons in the AN. The present results do not provide clear evidence that neurosteroids are involved in the action of ODN on POMC gene expression in the IL.
Garcia de Yebenes
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MRC Group in Molecular Endocrinology, CHUL Research Center, Québec, Canada.
Li
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Pelletier
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D000315:Adrenalectomy; D000818:Animals; D002352:Carrier Proteins; D002552:Cerebral Ventricles / Q000187:drug effects / Q000502:physiology*; D026261:Diazepam Binding Inhibitor; D013196:Dihydrotestosterone / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D018120:Finasteride / Q000494:pharmacology; D018755:GABA Agonists / Q000494:pharmacology*; D017403:In Situ Hybridization; D007275:Injections, Intravenous; D007276:Injections, Intraventricular; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D009479:Neuropeptides / Q000008:administration & dosage / Q000494:pharmacology*; D009919:Orchiectomy; D010446:Peptide Fragments; D010902:Pituitary Gland / Q000187:drug effects / Q000378:metabolism*; D011284:Pregnenolone / Q000008:administration & dosage / Q000494:pharmacology; D011333:Pro-Opiomelanocortin / Q000096:biosynthesis*; D012333:RNA, Messenger; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000502:physiology*; D014158:Transcription, Genetic / Q000187:drug effects*
D002352:Carrier Proteins; D026261:Diazepam Binding Inhibitor; D004791:Enzyme Inhibitors; D018755:GABA Agonists; D009479:Neuropeptides; D010446:Peptide Fragments; D012333:RNA, Messenger; D011963:Receptors, GABA-A; C067529:diazepam binding inhibitor (33-50); C018370:pregnenolone sulfate; D013196:Dihydrotestosterone; D018120:Finasteride; D011333:Pro-Opiomelanocortin; D011284:Pregnenolone; C009954:trilostane