Characterization of L‐2‐Amino‐4‐Phosphonobutanoate Action Following Sensitization by Quisqualate in Rat Hippocampal Slice Cultures

Abstract

An excitatory action of l-2-amino-4-phosphonobutanoate (l-AP4), a glutamate analogue, is observed following pre-exposure of tissue to quisqualate. We have studied the mechanism of sensitization of l-AP4 responses by quisqualate in voltage-clamped CA3 pyramidal cells in rat hippocampal slice cultures in the presence of tetrodotoxin. Prior to quisqualate addition, CA3 cells did not respond to l-AP4 (50 - 1000 microM). Following brief application of quisqualate (500 nM for 30 s), l-AP4 (50 - 200 microM) induced a complex excitatory response which could be obtained for >1 h. l-AP4 caused an ionotropic inward current associated with a conductance increase. This response was in part sensitive to 6-cyano-7-nitro-quinoxaline-2,3-dione (CNQX) and in part sensitive to d-2-amino-5-phosphonovalerate (d-AP5) and Mg2+ ions. At depolarizing potentials, in the presence of CNQX and d-AP5, l-AP4 caused excitation by depressing K+ currents, mimicking the metabotropic action of glutamate. This indicates that the action of l-AP4 is mediated by three different receptor types: N-methyl-d-aspartate (NMDA) receptors, alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionate (AMPA) receptors, and glutamatergic metabotropic receptors. The l-AP4 response persisted in solutions containing low Ca2+ and high Mg2+ concentrations or 100 - 200 microM Cd2+, suggesting that it is independent of extracellular Ca2+. We were unable to identify any substance other than quisqualate capable of sensitizing the l-AP4 action. This effect also occurred when quisqualate was applied in Ca2+-free solution or in solutions containing low concentrations of Na+ or Cl-. Sensitization of l-AP4 responses by quisqualate was not observed in acutely dissociated pyramidal cells recorded by means of the whole-cell recording mode, although ionotropic quisqualate responses were present. Sensitization was readily reversed by short applications of the endogenous excitatory amino acids glutamate, aspartate and homocysteate at concentrations of 10 - 100 microM. Our data are consistent with the hypothesis that the excitatory action of l-AP4 results from a Ca2+-independent release of endogenous excitatory amino acids from some presynaptic neuronal or glial site.

Quisqualate‐preferring metabotropic glutamate receptor activates Na(+)‐Ca2+ exchange in rat basolateral amygdala neurones.

“…IQuis is not likely to result from active uptake of quisqualate, as occurs with quisqualate sensitization of L-AP4 or L-AP5 responses in hippocampus (Charpak, Thompson, Giihwiler & Gerber, 1992;Schulte, Roon & Koerner, 1993). The sensitizing effect of quisqualate is observed in Ca2+-free solution, in low-Na+ solution, and when electrodes are filled with BAPTA (Charpak et al 1992). These data directly contrast with our observations of quisqualate effects on basolateral amygdala neurones.…”

“…Furthermore, while XIP exerted its effects on I membrane currents mediated through potassium conductances in response to baclofen and 1S,3R-ACPD were recorded, a finding suggesting specificity of XIP for IQUjS in basolateral amygdala neurones. The effect of XIP on IQuj", together with the cumulative Na+ and Ca2+ dependence and lack of a reversal potential, strongly suggest that IQui is mediated through activation of electrogenic Na+-Ca2+ (Charpak et al 1992). These data directly contrast with our observations of quisqualate effects on basolateral amygdala neurones.…”

Inhibition of a slow synaptic response by a metabotropic glutamate receptor antagonist in hippocampal CA3 pyramidal cells

“…1990). They fail, however, to modify the electrophysiological re sponses mediated by these receptors in the central nervous system (Stratton et al 1990;Crepel et al 1991;Charpak & Gahwiler 1991;Charpak et al 1992;Glaum & Miller 1992;Hu & Storm 1992;McCormick & von Krosigk 1992;Miles & Poncer 1993). This discrepancy may be due to the fact that the metabotropic glutamate receptors com prise at least six distinct members, and the subtypes controlling ion channel activity may differ from those linked to PLC.…”