title: Human brain cholecystokinin: release of cholecystokinin-like immunoreactivity (CCK-LI) from isolated cortical nerve endings and its modulation through GABA(B) receptors.
abstract: The release of cholecystokinin-like immunoreactivity (CCK-LI) in human brain was investigated using synaptosomes prepared from neocortical specimens removed during neurosurgery. CCK-LI basal release from superfused synaptosomes was increased 3 to 4-fold during depolarization with 15 mM KCI. The K(+)-evoked overflow of CCK-LI was strictly Ca(++)-dependent. The gamma-aminobutyric acidB (GABA(B)) receptor agonist (-)baclofen (0.3-100 microM) inhibited CCK-LI overflow in a concentration-dependent manner (EC50 = 2.20 microM; maximal effect: 45%). The novel GABA(B) receptor ligand CGP 47656 mimicked (-)baclofen (EC50 = 2.45 microM; maximal effect: 50%), whereas the GABA(A) agonist muscimol was ineffective up to 100 microM. The inhibitory effect of 10 microM (-)baclofen on the CCK-LI overflow was concentration-dependently prevented by two selective GABA(B) receptor antagonists, CGP 35348 (IC50 = 13.91 microM) and CGP 52432 (IC50 = 0.08 microM). The effect of 10 microM CGP 47656 was abolished by 1 microM CGP 52432. In experiments on [3H]GABA release, CGP 47656 behaved as an antagonist at the GABA(B) autoreceptors: added at 10 microM, it prevented the inhibitory effect of 10 microM (-)baclofen on the K+ (15 mM)-evoked release of [3H]GABA from human synaptosomes. We conclude that 1) the release of CCK-LI evoked from human brain tissue appears of neuronal origin; 2) the CCK-releasing terminal possess inhibitory presynaptic GABA(B) receptors; 3) these receptors differ pharmacologically from human neocortex GABA(B) autoreceptors, which are CGP 35348-insensitive (Fassio et al., 1994) but can be blocked by CGP 47656; 4) because cholecystokinin has been implicated in anxiety, the GABA(B) receptors here characterized may represent targets for novel anxiolytic agents.
authors.affiliation: Istituto di Farmacologia e Farmacognosia, Università degli Studi di Genova, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Raiteri
authors.forename: G
authors.initials: G
authors.lastname: Bonanno
authors.forename: P
authors.initials: P
authors.lastname: Paudice
authors.forename: P
authors.initials: P
authors.lastname: Cavazzani
authors.forename: G
authors.initials: G
authors.lastname: Schmid
mesh_terms: D001596:Benzylamines / Q000494:pharmacology; D001921:Brain / Q000378:metabolism*; D002118:Calcium / Q000494:pharmacology; D002540:Cerebral Cortex / Q000276:immunology / Q000378:metabolism*; D002766:Cholecystokinin / Q000276:immunology*; D004305:Dose-Response Relationship, Drug; D018756:GABA Antagonists / Q000494:pharmacology; D006801:Humans; D009412:Nerve Fibers / Q000378:metabolism; D010721:Phosphinic Acids / Q000494:pharmacology; D018080:Receptors, GABA-B / Q000187:drug effects*
chemical_list: D001596:Benzylamines; D018756:GABA Antagonists; D010721:Phosphinic Acids; D018080:Receptors, GABA-B; C083008:CGP 52432; D002766:Cholecystokinin; D002118:Calcium