In vivo microdialysis study of GABA A and GABa B receptors modulating the glutamate receptor/NO/ cyclic GMP pathway in the rat hippocampus

Abstract

Intrahippocampal perfusion of bicuculline (50 μM) in Mg 2+-free medium caused elevation of extracellular cGMP and epileptic-like behaviour. Both effects were partially prevented by blocking NMDA receptors with MK-801 or Mg 2+ ions. Similarly, the GABA B receptor antagonists CGP52432 (0.1–30 μM) and CGP35348 (0.3-1 mM) evoked increases of extracellular cGMP. CGP52432 also elicited behavioural responses ranging from wet dog shakes to convulsions. MK-801 or Mg 2+ ions reduced the effects of CGP52432. Local application of muscimol (100–300 μM) or (−)baclofen (300 μM) caused inhibition of extracellular cGMP. Administration of the AMPA/kainate receptor antagonist NBQX (100 μM) caused cGMP elevation which was almost abolished by co-perfusion of muscimol and (−)baclofen. In the presence of physiological Mg 2+, perfusion of AMPA (30 μM) failed to affect cGMP levels, although rats displayed wet dog shakes episodes. When AMPA was co-perfused with low concentrations of bicuculline or CGP52432, cGMP elevations were observed in 60% of the rats. Addition of both antagonists to AMPA resulted in 85% of rats displaying a cGMP response. To conclude: (a) extracellular hippocampal cGMP is controlled by inhibitory GABA A and GABa b receptors tonically activated through GABAergic interneurons receiving AMPA/kainate-mediated glutamatergic inputs; (b) the GABAergic receptors are not endogenously saturated and can be further stimulated by exogenous agonists; (c) blockade of the GABA-mediated inhibition causes increase of cGMP and epileptic-like behaviour, due largely to endogenous activation of NMDA receptors; (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.