The actions of phenylglycine derived metabotropic glutamate receptor antagonists on multiple (1S,3R)-ACPD responses in the rat nucleus of the tractus solitarius.
The effects of the metabotropic glutamate receptor (mGluR) agonist (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid [(1S,3R)-ACPD] and a series of phenylglycine-derived putative mGluR antagonists were examined on electrophysiological responses mediated by glutamate and GABA receptors in the nucleus of the tractus solitarius (NTS) in transverse brainstem slices of the rat. Monosynaptic excitatory currents (EPSC's) evoked by electrical stimulation in the region of the tractus solitarius (TS) were reduced in the presence of (1S,3R)-ACPD in > 90% of neurons recorded in the dorsomedial subdivision of the NTS adjacent to the area postrema (AP). Monosynaptic evoked inhibitory currents (IPSC's) were similarly inhibited by (1S,3R)-ACPD. The inward current evoked by pressure application of alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (IAMPA) was potentiated in the presence of (1S,3R)-ACPD, whereas the outward current evoked by the gamma-amino-butyric acid-A (GABA-A) receptor agonist muscimol (IMUSC) was inhibited. (1S,3R)-APCD also produced a postsynaptic inward current (IK(ACPD)) associated with a decrease in membrane conductance in approximately 50% of cells. The novel mGluR antagonists (S)-4-carboxy-3-hydroxy-phenylglycine (4C3H-PG), (R,S)-4-carboxy-phenylglycine (4C-PG) and (R,S)-alpha-methyl-4-carboxy-phenylglycine (alpha M4C-PG) reversibly antagonized the effects of (1S,3R)-ACPD on EPSC's IPSC's, IAMPA and IMUSC. The first two compounds also displayed weak agonist activity. However, none of the antagonists significantly inhibited IK(ACPD) at concentrations which blocked (1S,3R)-ACPD effects on synaptic transmission. These results suggest that pharmacologically distinct mGluR's may be present in the NTS.
Glaum
S R
SR
Department of Pharmacological and Physiological Sciences, University of Chicago, IL 60637.
Sunter
D C
DC
Udvarhelyi
P M
PM
Watkins
J C
JC
Miller
R J
RJ
D000818:Animals; D001933:Brain Stem / Q000187:drug effects / Q000502:physiology; D003515:Cycloleucine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004558:Electric Stimulation; D005071:Evoked Potentials / Q000187:drug effects; D018691:Excitatory Amino Acid Antagonists; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D066298:In Vitro Techniques; D008564:Membrane Potentials / Q000187:drug effects; D009118:Muscimol / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D009498:Neurotoxins / Q000494:pharmacology*; D051381:Rats; D011963:Receptors, GABA-A / Q000187:drug effects / Q000502:physiology; D017552:Solitary Nucleus / Q000187:drug effects / Q000502:physiology*; D013329:Structure-Activity Relationship; D009435:Synaptic Transmission / Q000187:drug effects; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000494:pharmacology
D018691:Excitatory Amino Acid Antagonists; D009498:Neurotoxins; D011963:Receptors, GABA-A; D003515:Cycloleucine; C036361:1-amino-1,3-dicarboxycyclopentane; D009118:Muscimol; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D005998:Glycine