Selective block of rat and human neocortex GABA(B) receptors regulating somatostatin release by a GABA(B) antagonist endowed with cognition enhancingactivity

Previously, we have shown that presynaptic GABA(B) receptors regulating the release of various transmitters from CNS terminals can be differentially b locked by GABA(B) antagonists suggesting the existence of pharmacologically distinct GABA(B) receptor subtypes. We here examined the ability of CGP 36 742 [(3-aminopropyl)n-butylphosphinic acid], a selective GABA(B) antagonist endowed with cognition enhancing activity, to block release-regulating GAB A(B) receptors. In particular, CGP 36742 was tested against the inhibition of the depolarization-evoked release of GABA(B) glutamate, cholecystokinin and somatostatin produced by (-)baclofen in rat and human neocortex axon te rminals. CGP 36742 potently antagonized (IC50 = 0.14 mu M) the inhibition b y (-)baclofen of somatostatin release from superfused rat neocortex synapto somes. In contrast, the effects of(-)baclofen on GABA(B) glutamate and chol ecystokinin release were insensitive to CGP 36742, at concentrations of up to 100 mu M. In human neocortex synaptosomes CGP 36742 exhibited a pattern of selectivity identical to that in rat synaptosomes, although the antagoni st was at least 10-fold less potent in human than in rat brain. CGP 36742 i s the first compound displaying great selectivity for the GABA(B) presynapt ic receptors regulating somatostatin release. Considering the proposed impl ication of the neuropeptide in cognitive processes, disinhibition of somato statin release merits consideration as one of the mechanisms possibly invol ved in the behavioral activity of CGP 36742. (C) 1999 Elsevier Science Ltd. All rights reserved.