IN-VIVO MICRODIALYSIS STUDY OF GABA(A) AND GABA(B) RECEPTORS MODULATING THE GLUTAMATE RECEPTOR NO/CYCLIC GMP PATHWAY IN THE RAT HIPPOCAMPUS/

Intrahippocampal perfusion of bicuculline (50 mu M) in Mg2+-free mediu m caused elevation of extracellular cGMP and epileptic-like behaviour. Both effects were partially prevented by blocking NMDA receptors with MK-801 or Mg2+ ions. Similarly, the GABAB receptor antagonists CGP524 32 (0.1-30 mu M) and CGP35348 (0.3-1mM) evoked increases of extracellu lar cGMP. CGP52432 also elicited behavioural responses ranging from we t dog shakes to convulsions. MK-801 or Mg2+ ions reduced the effects o f CGP52432. Local application of muscimol (100-300 mu M) or (-)baclofe n (300 mu M) caused inhibition of extracellular cGMP. Administration o f the AMPA/kainate receptor antagonist NBQX (100 mu M) caused cGMP ele vation which was almost abolished by co-perfusion of muscimol and (-)b aclofen. In the presence of physiological Mg2+, perfusion of AMPA (30 mu M) failed to affect cGMP levels, although rats displayed wet dog sh akes episodes. When AMPA was co-perfused with low concentrations of bi cuculline or CGP52432, cGMP elevations were observed in 60% of the rat s. Addition of both antagonists to AMPA resulted in 85% of rats displa ying a cGMP response. To conclude: (a) extracellular hippocampal cGMP is controlled by inhibitory GABA(A) and GABA(B) receptors tonically ac tivated through GABAergic interneurons receiving AMPA/kainate-mediated glutamatergic inputs; (b) the GABAergic receptors are not endogenousl y saturated and can be further stimulated by exogenous agonists; (c) b lockade of the GABA-mediated inhibition causes increase of cGMP and ep ileptic-like behaviour, due largely to endogenous activation of NMDA r eceptors; (d) reproducible cGMP responses to AMPA can be observed when the inhibitory GABAergic inputs to the NO/guanylyl cyclase system are blocked, confirming the previously proposed existence of AMPA/kainate receptors able to increase the nucleotide synthesis. (C) 1997 Elsevie r Science Ltd.