Studies on pituitary melanotrophs reveal the novel GABA B antagonist CGP 35-348 to be the first such compound effective on endocrine cells

Abstract

One obstacle to understanding the action and physiological significance of the responsiveness of various endocrine cells to $\gamma $-aminobutyric acid (GABA) has been that previously available substances, all active as GABA$_{\text{B}}$ 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 GABA$_{\text{B}}$ agonist. Analysis, in toad, showed CGP 35-348 did not affect responses to GABA$_{\text{A}}$ 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 GABA$_{\text{A}}$ 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.