GABA(A), but not NMDA, receptors modulate in vivo NO-mediated cGMP synthesis in the rat cerebral cortex

We have investigated the functional relationships between NMDA receptors and the NOS/sGC system in the rat pre-frontal cortex in vivo by microdialysis. cGMP basal levels were sensitive to NOS or sGC inhibitors (L-NARG or ODQ) or NO donors (SNAP) when enzymatic breakdown was blocked by the phosphodiesterase inhibitor IBMX, indicating that basal cGMP production derives, at least in part, from the NOS/sGC pathway activity and that the pre-frontal cortex possesses a very efficient degradation system for cGMP. The glutamate receptor agonist NMDA did not alter extracellular cGMP either in absence or presence of IBMX. cGMP was not augmented when NMDA was co-infused with the NOS substrate L-arginine, the glycine site agonist d-serine or the glutamate receptor agonist AMPA. Interestingly, the selective GABA(A) receptor antagonist bicuculline enhanced cGMP production, revealing that the cortical NOS/sGC system is tonically inhibited by endogenous GABA. However, in the presence of bicuculline, NMDA did not increase extracellular cGMP. In the presence of bicuculline, blockade of 5-HT1/2 receptors, known to inhibit the NMDA/NOS/sGC pathway, with the antagonist methiothepin did not unmask cGMP elevations by NMDA. Thus, it would seem that NMDA receptors do not regulate cortical NOS/sGC activity that, on the other hand, is modulated by endogenous GABA acting at GABA(A) receptors.