Studies on pituitary melanotrophs reveal the novel GABAB antagonist CGP 35-348 to be the first such compound effective on endocrine cells.
One obstacle to understanding the action and physiological significance of the responsiveness of various endocrine cells to gamma-aminobutyric acid (GABA) has been that previously available substances, all active as GABAB antagonists in the nervous system, are ineffective on endocrine cells. The introduction of a potent new member of this class, CGP 35-348, of very different chemical structure, encouraged us to examine its effect on endocrine cells. For this purpose, we studied melanotroph secretion from pituitary neurointermediate lobes. We found that CGP 35-348, in contrast to previously available members of this class, suppressed completely, in rat and toad, secretory responses to baclofen, the classic GABAB agonist. Analysis, in toad, showed CGP 35-348 did not affect responses to GABAA agonists (muscimol; isoguvacine), dopamine, or neuropeptide Y. When tested against GABA, the physiological ligand present in the innervation of melanotrophs (along with dopamine and neuropeptide Y), CGP 35-348 completely suppressed the secretory response, which, in toad, is purely inhibitory and unaffected by bicuculline, the specific GABAA antagonist. In addition, CGP 35-348 unmasked a stimulant effect that bicuculline blocked. In CGP 35-348, we thus have a new tool with which to analyse responses to GABA and their physiological involvement in endocrine cells.
Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06510.
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D000818:Animals; D001418:Baclofen / Q000031:analogs & derivatives / Q000494:pharmacology; D001640:Bicuculline / Q000494:pharmacology; D003624:Darkness; D018756:GABA Antagonists; D058787:GABA-A Receptor Antagonists; D007700:Kinetics; D008297:Male; D009074:Melanocyte-Stimulating Hormones / Q000096:biosynthesis / Q000378:metabolism*; D008715:Methionine / Q000378:metabolism; D009118:Muscimol / Q000494:pharmacology; D009943:Organophosphorus Compounds / Q000494:pharmacology*; D010902:Pituitary Gland / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D014982:Xenopus laevis
D018756:GABA Antagonists; D058787:GABA-A Receptor Antagonists; D009943:Organophosphorus Compounds; D009118:Muscimol; C066430:CGP 35348; D009074:Melanocyte-Stimulating Hormones; D008715:Methionine; D001418:Baclofen; C057491:2-hydroxysaclofen; D001640:Bicuculline