INHIBITION OF PHOSPHOPROTEIN PHOSPHATASES BLOCKS METABOTROPIC GLUTAMATE-RECEPTOR EFFECTS IN THE RAT NUCLEUS-TRACTUS-SOLITARII

Whole-cell recordings were made from dorsomedial nucleus tractus solit arii neurons in thin coronal medullary slices of the rat, at the level of the area postrema. Monosynaptic excitatory postsynaptic currents ( EPSCs) were evoked in the tractus solitarius by electrical stimulation in the presence of D-2-amino-5-phosphonopentanoic acid (AP5) and bicu culline. Currents were also evoked by pressure ejection of pha-amino-3 -hydroxy-5-methylisoxazole-4-propionate (AMPA) in the presence of AP5, bicuculline, and tetrodotoxin or muscimol in the presence of 6,7-dini troquinoxaline-2,3-dione and AP5. The metabotropic glutamate receptor (mGluR) agonist (1S,3R)-1-aminocyclopentane-1,3-dicarboxylate [(1S,3R) -ACPD] reversibly depressed the EPSC and muscimol currents and reversi bly potentiated AMPA currents. The effects of (IS,SR)-ACPD were blocke d in the presence of a low concentration of the phosphoprotein phospha tase (PP)1 and PP2A inhibitor okadaic acid (OA) but not by a low conce ntration of the PP inhibitor calyculin A. The immunosuppressant agent FK506 failed to block (1S,3R)-ACPD effects on AMPA currents. However, (IS,3R)-ACPD applied in the presence of FK506 produced a reversible po tentiation of muscimol currents. We previously demonstrated that the c ell-permeant cGMP analog 8-Br-cGMP can mimic many of the effects of (1 S,3R)-ACPD. OA antagonized the effects of 8-Br-cGMP in the present inv estigation. finally, we previously demonstrated that brief tetanic sti mulation results in the activation of a presynaptic mGluR autoreceptor and depression of subsequently evoked EPSCs. OA similarly blocked tet anus-induced depression of EPSCs. These findings suggest that mGluRs o n tractus solitarius afferents and first-order nucleus tractus solitar ii neurons may modulate glutamate release and AMPA and gamma-aminobuty ric acid type A receptor activity via activation of one or more PPs, s uch as PP2A and/or calcineurin.