Potentiation of NMDA receptor function through somatostatin release: a possible mechanism for the cognition-enhancing activity of GABA(B) receptor antagonists

CGP 36742 is a weak GABA(B) receptor antagonist. However, it improves cogni tive performances at low doses; it blocks GABA(B) receptors potently and se lectively on somatostatinergic terminals; it prevents kynurenate from antag onising NMDA-induced release of noradrenaline from rat brain slices potentl y. We here investigated whether and how somatostatin plays a role in the CG P 36742 activity. CGP 36742 increased the somatostatin-like immunoreactivit y (SRIF-LI) release from hippocampal slices exposed to NMDA. In the kynuren ate test with rat hippocampal slices SRIF-14 mimicked the effect of CGP 367 42. CGP 36742 lost its activity in rats whose somatostatin content had been depleted with cysteamine. Exogenous SRIF-14 reverted kynurenate antagonism in somatostatin-depleted slices. L362855, an sst(5) receptor agonist, but not the selective sst(1)-sst(4) agonists, L797591, L779976, L796778 and L80 3087, displayed activity in the kynurenate test. The effects of CGP 36742, SRIF-14 and L362855 were antagonised by the sst(5)-preferring antagonist BI M-23056. The protein kinase C inhibitor GF 109203X prevented the reversal o f the kynurenate antagonism by CGP 36742 or SRIF-14. In conclusion, by sele ctively blocking GABAB receptors on somatostatinergic terminals, CGP 36742 may disinhibit somatostatin release; the consequent activation of sst5 rece ptors would potentiate the function of NMDA receptors coexisting with sst(5 ) receptors on noradrenergic neurons. (C) 2001 Elsevier Science Ltd. All ri ghts reserved.