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 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.
Pittaluga
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A
Dipartimento di Medicina Sperimentale, Sezione di Farmacologia e Tossicologia, Università di Genova, Viale Cembrano 4, 16148 Genova, Italy.
Feligioni
M
M
Ghersi
C
C
Gemignani
A
A
Raiteri
M
M
D000818:Animals; D003071:Cognition / Q000187:drug effects*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D018756:GABA Antagonists / Q000494:pharmacology; D058788:GABA-B Receptor Antagonists; D066298:In Vitro Techniques; D008297:Male; D009638:Norepinephrine / Q000378:metabolism; D009943:Organophosphorus Compounds / Q000494:pharmacology; D011493:Protein Kinase C / Q000378:metabolism; D011863:Radioimmunoassay; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000187:drug effects; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists*; D017481:Receptors, Somatostatin / Q000187:drug effects / Q000378:metabolism; D012844:Sincalide / Q000494:pharmacology; D013004:Somatostatin / Q000378:metabolism*; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism
D018691:Excitatory Amino Acid Antagonists; D018756:GABA Antagonists; D058788:GABA-B Receptor Antagonists; D009943:Organophosphorus Compounds; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; D017481:Receptors, Somatostatin; C079148:(3-aminopropyl)(n-butyl)phosphinic acid; D013004:Somatostatin; D011493:Protein Kinase C; D012844:Sincalide; D009638:Norepinephrine