title: Pharmacological discrimination between gamma-aminobutyric acid type B receptors regulating cholecystokinin and somatostatin release from rat neocortex synaptosomes.
abstract: The gamma-aminobutyric acid (GABA)B receptors modulating the depolarization-evoked release of somatostatin (SRIF) or cholecystokinin (CCK) from superfused rat cerebrocortical synaptosomes have been characterized pharmacologically. GABA inhibited the 15 mM KCl-evoked overflow of both SRIF and CCK; the EC50 values were 1.3 microM and 1.4 microM, respectively. The GABAB receptor agonist (-)-baclofen also diminished the release of SRIF (EC50 = 1.9 microM) and CCK (EC50 = 2.6 microM). The novel compound CGP 47656, a highly selective GABAB receptor ligand, inhibited the release of SRIF, with its affinity and efficacy being similar to those of GABA or (-)-baclofen; however, the compound was unable to affect CCK release even when tested at 300 microM. The GABAB receptor antagonist phaclofen prevented, with identical affinities, the effects of (-)-baclofen on SRIF (pKb = 4.9) and CCK (pKb = 4.8) release. The same was true for CGP 35348, another GABAB receptor antagonist, which blocked (-)-baclofen with a pKb value of 6.1 at both the GABAB receptors regulating SRIF and CCK release. The effects of (-)-baclofen were also counteracted by the novel GABAB receptor antagonist CGP 52432. However, the affinity of the drug at the GABAB receptors modulating SRIF release (pKb = 6.2) was about 30-fold lower than that at the receptors regulating CCK release (pKb = 7.6). The data suggest that the GABAB receptors situated on nerve terminals releasing SRIF and CCK display pharmacological heterogeneity and may represent different subtypes of GABAB receptors.
authors.affiliation: Institute of Pharmacology and Pharmacognosy, University of Genoa, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Gemignani
authors.forename: P
authors.initials: P
authors.lastname: Paudice
authors.forename: G
authors.initials: G
authors.lastname: Bonanno
authors.forename: M
authors.initials: M
authors.lastname: Raiteri
mesh_terms: D000818:Animals; D001418:Baclofen / Q000031:analogs & derivatives / Q000494:pharmacology; D001596:Benzylamines / Q000494:pharmacology; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D002766:Cholecystokinin / Q000378:metabolism*; D018755:GABA Agonists / Q000494:pharmacology*; D058787:GABA-A Receptor Antagonists; D058788:GABA-B Receptor Antagonists; D008024:Ligands; D008297:Male; D009943:Organophosphorus Compounds / Q000494:pharmacology; D010721:Phosphinic Acids; D051381:Rats; D017207:Rats, Sprague-Dawley; D018080:Receptors, GABA-B / Q000187:drug effects* / Q000378:metabolism; D013004:Somatostatin / Q000378:metabolism*; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism*; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
chemical_list: C089748:3-aminopropyl(difluoromethyl)phosphinic acid; D001596:Benzylamines; D018755:GABA Agonists; D058787:GABA-A Receptor Antagonists; D058788:GABA-B Receptor Antagonists; D008024:Ligands; D009943:Organophosphorus Compounds; D010721:Phosphinic Acids; D018080:Receptors, GABA-B; C052329:phaclofen; C083008:CGP 52432; D013004:Somatostatin; D005680:gamma-Aminobutyric Acid; C066430:CGP 35348; D002766:Cholecystokinin; D001418:Baclofen