ZINC PROTOPORPHYRIN-IX BLOCKS THE EFFECTS OF METABOTROPIC GLUTAMATE-RECEPTOR ACTIVATION IN THE RAT NUCLEUS-TRACTUS-SOLITARII

The effects of the metabotropic glutamate receptor agonist (1S,3R)-1-a minocyclopentane-1,3-dicarboxylic acid [(1S,3R)-ACPD] on ionic current responses produced by ionotropic glutamate and -/-aminobutyric acid ( GABA)A receptor activation in the nucleus of the tractus solitarius (N TS) were examined. Recordings were made in the dorsomedial subdivision of the NTS adjacent to the area postrema in transverse brainstem slic es of the rat. (1S,3R)-ACPD produced a small inward current (I(ACPD)) associated with a decrease in conductance in approximately 50% of reco rdings. Monosynaptic excitatory postsynaptic currents (EPSCs) evoked b y electrical stimulation in the region of the tractus solitarius in th e presence Of D-amino-5-phosphono-pentanoic acid and bicuculline were reversibly reduced by (1S,3R)-ACPD in >90% of cells. The inward curren t evoked by pressure application of lpha-amino-3-hydroxy-5-methyl-4-is oxazolepropionic acid (AMPA) (I(AMPA)) was potentiated in the presence of (1S,3R)-ACPD, whereas the outward current evoked by the GABA(A) re ceptor agonist muscimol (I(MUSC)) was inhibited. We have previously de monstrated that these effects may involve the activation of soluble gu anylate cyclase. The diffusible second messengers nitric oxide and car bon monoxide are known to activate soluble guanylate cyclase. The nitr ic oxide synthase inhibitor L-omega-nitroarginine failed to inhibit re sponses to (1S,3R)-ACPD. The selective heme oxygenase inhibitor Zn-pro toporphyrin-IX, which would be expected to block the production of car bon monoxide, antagonized the effects of (1S,3R)-ACPD on EPSCS, I(AMPA ), and I(MUSC). However, I(ACPD) was not blocked. A relatively inactiv e metalloprotoporphyrin, Cu-protoporphyrin-IX, was ineffective. A cell -permeant form of cGMP, 8-Br-cGMP, inhibited EPSCs, I(AMPA), and I(MUS C) in the presence of Zn-protoporphyrin-IX but did not induce an inwar d current. These results further support the hypothesis that multiple metabotropic glutamate receptors exist in the NTS, and they suggest th at one of these may be coupled to the activation of a soluble guanylat e cyclase via the liberation of an easily diffusible second messenger such as carbon monoxide.