Human brain somatostatin release from isolated cortical nerve endings and its modulation through GABA(B) receptors

1 The release of somatostatin-like immunoreactivity (SRIF-LI) in the human brain was studied in synaptosomal preparations from fresh neocortical specimens obtained from patients undergoing neurosurgery to remove deeply sited tumours. 2 The basal outflow of SRIF-LI from superfused synaptosomes was increased about 3 fold during exposure to a depolarizing medium containing 15 mM KCl. The K+-evoked overflow of SRIF-LI was almost totally dependent on the presence of Ca2+ in the superfusion medium. 3 The GABA(B) receptor agonist, (-)-baclofen (0.3-100 mu M), inhibited the overflow of SRIF-LI in a concentration-dependent manner (EC(50) = 1.84+/-0.20 mu M; maximal effect. about 50%). The novel GABA(B) receptor ligand, 3-aminopropyl(difluoromethyl)phosphinic acid (CGP 47656) mimicked (-)-baclofen in inhibiting the SRIF-LI overflow (EC(50)=3.06+/-0.52 mu M; maximal effect: about 50%), whereas the GABA(A) receptor agonist, muscimol, was ineffective up to 100 mu M. 4 The inhibition by 10 mu M (-)-baclofen of the K+-evoked SRIF-LI overflow was concentration-dependently prevented by two selective GABA, receptor antagonists, 3-amino-propyl (diethoxymethyl)phosphinic acid (CGP 35348) (IC50 = 24.40+/-2.52 mu M) and [3-[[(3,4-dichlorophenyl) methyl]amino]propyl] (diethoxymethyl) phosphinic acid (CGP 52432) (IC50=0.06+/-0.005 mu M). 5 The inhibition of SRIF-LI overflow caused by 10 mu M CGP 47656 was abolished by 1 mu M CGP 52432. 6 When human synaptosomes were labelled with [H-3]-GABA and depolarized in superfusion with 15 mM KCl, the inhibition by 10 mu M (-)-baclofen of the depolarization-evoked [H-3]-GABA overflow was largely prevented by 10 mu M CGP 47656 which therefore behaved as an autoreceptor antagonist. 7 In conclusion: (a) the characteristics of SRIF-LI release from synaptosomal preparations of human neocortex are compatible with a neuronal origin; (b) the nerve terminals releasing the neuropeptide possess inhibitory receptors of the GABAB type; (c) these receptors differ pharmacologically from the GABA(B) autoreceptors present on human neocortex nerve terminals since the latter have been shown to be CGP 35348-insensitive but can be blocked by CGP 47656.