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

Previously, we have shown that presynaptic GABA(B) receptors regulating the release of various transmitters from CNS terminals can be differentially blocked by GABA(B) antagonists suggesting the existence of pharmacologically distinct GABA(B) receptor subtypes. We here examined the ability of CGP 36742 [(3-aminopropyl)n-butylphosphinic acid], a selective GABA(B) antagonist endowed with cognition enhancing activity, to block release-regulating GABA(B) receptors. In particular, CGP 36742 was tested against the inhibition of the depolarization-evoked release of GABA, glutamate, cholecystokinin and somatostatin produced by (-)baclofen in rat and human neocortex axon terminals. CGP 36742 potently antagonized (IC50 = 0.14 microM) the inhibition by (-)baclofen of somatostatin release from superfused rat neocortex synaptosomes. In contrast, the effects of (-)baclofen on GABA, glutamate and cholecystokinin release were insensitive to CGP 36742, at concentrations of up to 100 microM. In human neocortex synaptosomes CGP 36742 exhibited a pattern of selectivity identical to that in rat synaptosomes, although the antagonist was at least 10-fold less potent in human than in rat brain. CGP 36742 is the first compound displaying great selectivity for the GABA(B) presynaptic receptors regulating somatostatin release. Considering the proposed implication of the neuropeptide in cognitive processes, disinhibition of somatostatin release merits consideration as one of the mechanisms possibly involved in the behavioral activity of CGP 36742.