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

ABSTRACT

CGP 36742 is a weak GABA(B) receptor antagonist. However, it improves cognitive performances at low doses; it blocks GABA(B) receptors potently and selectively on somatostatinergic terminals; it prevents kynurenate from antagonising NMDA-induced release of noradrenaline from rat brain slices potently. We here investigated whether and how somatostatin plays a role in the CGP 36742 activity. CGP 36742 increased the somatostatin-like immunoreactivity (SRIF-LI) release from hippocampal slices exposed to NMDA. In the kynurenate test with rat hippocampal slices SRIF-14 mimicked the effect of CGP 36742. 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 L803087, displayed activity in the kynurenate test. The effects of CGP 36742, SRIF-14 and L362855 were antagonised by the sst(5)-preferring antagonist BIM-23056. The protein kinase C inhibitor GF 109203X prevented the reversal of the kynurenate antagonism by CGP 36742 or SRIF-14. In conclusion, by selectively blocking GABA(B) receptors on somatostatinergic terminals, CGP 36742 may disinhibit somatostatin release; the consequent activation of sst(5) receptors would potentiate the function of NMDA receptors coexisting with sst(5) receptors on noradrenergic neurons.