Characterization of the inhibition of excitatory amino acid-induced neurotransmitter release in the rat striatum by phencyclidine-like drugs

L. D. Snell, K. M. Johnson

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179 Citations (Scopus)

Abstract

In the present study, the authors found that, in Mg++-free buffer, N-methyl-D-aspartate (NMDA) was able to evoke the Ca++-dependent and tetrodotoxin-sensitive release of striatal acetylcholine (ACh), presumably via interaction with receptors on cholinergic interneurons. In Mg++-free buffer containing pargyline, NMDA also evoked a Ca++-dependent and tetrodotoxin-sensitive release of striatal [3H]dopamine (DA). Phencyclidine (PCP) and physiological concentrations of Mg++ (1.2 mM) also inhibited ACh release evoked by L-glutamate, L-aspartate and DL-homocysteate, but not ACh release evoked by the glutamate analogs quisqualate and kainate, suggesting that PCP is selective for the magnesium-sensitive, NMDA-preferring glutamate-aspartate receptor subtype. Comparison of PCP inhibition of NMDA-stimulated ACh and DA release with that produced by the competitive NMDA antagonist 2-amino-5-phosphonovalerate indicates that PCP is probably not altering release by a direct action on the NMDA recognition site. The ability of 2-amino-5-phosphonovalerate, but not PCP, to prevent desensitization of NMDA-induced ACh release is consistent with this interpretation. Binding studies did, however, reveal a reduction in the apparent affinity of the PCP binding site by high concentrations of NMDA. This may suggest an allosteric link between the PCP-sigma receptor and the NMDA-type glutamate-aspartate receptor. The receptors mediating excitatory amino acid-induced DA release were somewhat less selective than those on cholinergic neurons in their sensitivity to both Mg++ and PCP. Structure-activity-relationship studies suggested that the inhibition of ACh and DA release evoked by NMDA involves binding to the PCP-sigma receptor. Thus, the PCP-sigma receptor and the NMDA-preferring receptor both may modulate a Mg++-sensitive ionic conductance channel in an opposing manner.

Original languageEnglish (US)
Pages (from-to)938-946
Number of pages9
JournalJournal of Pharmacology and Experimental Therapeutics
Volume238
Issue number3
StatePublished - 1986

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Phencyclidine
Excitatory Amino Acids
N-Methylaspartate
Neurotransmitter Agents
Acetylcholine
Phencyclidine Receptors
Pharmaceutical Preparations
sigma Receptors
Dopamine
Glutamate Receptors
2-Amino-5-phosphonovalerate
Corpus Striatum
Tetrodotoxin
Glutamic Acid
Buffers
Quisqualic Acid
Pargyline
Cholinergic Neurons
Kainic Acid
Cholinergic Receptors

ASJC Scopus subject areas

  • Pharmacology

Cite this

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title = "Characterization of the inhibition of excitatory amino acid-induced neurotransmitter release in the rat striatum by phencyclidine-like drugs",
abstract = "In the present study, the authors found that, in Mg++-free buffer, N-methyl-D-aspartate (NMDA) was able to evoke the Ca++-dependent and tetrodotoxin-sensitive release of striatal acetylcholine (ACh), presumably via interaction with receptors on cholinergic interneurons. In Mg++-free buffer containing pargyline, NMDA also evoked a Ca++-dependent and tetrodotoxin-sensitive release of striatal [3H]dopamine (DA). Phencyclidine (PCP) and physiological concentrations of Mg++ (1.2 mM) also inhibited ACh release evoked by L-glutamate, L-aspartate and DL-homocysteate, but not ACh release evoked by the glutamate analogs quisqualate and kainate, suggesting that PCP is selective for the magnesium-sensitive, NMDA-preferring glutamate-aspartate receptor subtype. Comparison of PCP inhibition of NMDA-stimulated ACh and DA release with that produced by the competitive NMDA antagonist 2-amino-5-phosphonovalerate indicates that PCP is probably not altering release by a direct action on the NMDA recognition site. The ability of 2-amino-5-phosphonovalerate, but not PCP, to prevent desensitization of NMDA-induced ACh release is consistent with this interpretation. Binding studies did, however, reveal a reduction in the apparent affinity of the PCP binding site by high concentrations of NMDA. This may suggest an allosteric link between the PCP-sigma receptor and the NMDA-type glutamate-aspartate receptor. The receptors mediating excitatory amino acid-induced DA release were somewhat less selective than those on cholinergic neurons in their sensitivity to both Mg++ and PCP. Structure-activity-relationship studies suggested that the inhibition of ACh and DA release evoked by NMDA involves binding to the PCP-sigma receptor. Thus, the PCP-sigma receptor and the NMDA-preferring receptor both may modulate a Mg++-sensitive ionic conductance channel in an opposing manner.",
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N2 - In the present study, the authors found that, in Mg++-free buffer, N-methyl-D-aspartate (NMDA) was able to evoke the Ca++-dependent and tetrodotoxin-sensitive release of striatal acetylcholine (ACh), presumably via interaction with receptors on cholinergic interneurons. In Mg++-free buffer containing pargyline, NMDA also evoked a Ca++-dependent and tetrodotoxin-sensitive release of striatal [3H]dopamine (DA). Phencyclidine (PCP) and physiological concentrations of Mg++ (1.2 mM) also inhibited ACh release evoked by L-glutamate, L-aspartate and DL-homocysteate, but not ACh release evoked by the glutamate analogs quisqualate and kainate, suggesting that PCP is selective for the magnesium-sensitive, NMDA-preferring glutamate-aspartate receptor subtype. Comparison of PCP inhibition of NMDA-stimulated ACh and DA release with that produced by the competitive NMDA antagonist 2-amino-5-phosphonovalerate indicates that PCP is probably not altering release by a direct action on the NMDA recognition site. The ability of 2-amino-5-phosphonovalerate, but not PCP, to prevent desensitization of NMDA-induced ACh release is consistent with this interpretation. Binding studies did, however, reveal a reduction in the apparent affinity of the PCP binding site by high concentrations of NMDA. This may suggest an allosteric link between the PCP-sigma receptor and the NMDA-type glutamate-aspartate receptor. The receptors mediating excitatory amino acid-induced DA release were somewhat less selective than those on cholinergic neurons in their sensitivity to both Mg++ and PCP. Structure-activity-relationship studies suggested that the inhibition of ACh and DA release evoked by NMDA involves binding to the PCP-sigma receptor. Thus, the PCP-sigma receptor and the NMDA-preferring receptor both may modulate a Mg++-sensitive ionic conductance channel in an opposing manner.

AB - In the present study, the authors found that, in Mg++-free buffer, N-methyl-D-aspartate (NMDA) was able to evoke the Ca++-dependent and tetrodotoxin-sensitive release of striatal acetylcholine (ACh), presumably via interaction with receptors on cholinergic interneurons. In Mg++-free buffer containing pargyline, NMDA also evoked a Ca++-dependent and tetrodotoxin-sensitive release of striatal [3H]dopamine (DA). Phencyclidine (PCP) and physiological concentrations of Mg++ (1.2 mM) also inhibited ACh release evoked by L-glutamate, L-aspartate and DL-homocysteate, but not ACh release evoked by the glutamate analogs quisqualate and kainate, suggesting that PCP is selective for the magnesium-sensitive, NMDA-preferring glutamate-aspartate receptor subtype. Comparison of PCP inhibition of NMDA-stimulated ACh and DA release with that produced by the competitive NMDA antagonist 2-amino-5-phosphonovalerate indicates that PCP is probably not altering release by a direct action on the NMDA recognition site. The ability of 2-amino-5-phosphonovalerate, but not PCP, to prevent desensitization of NMDA-induced ACh release is consistent with this interpretation. Binding studies did, however, reveal a reduction in the apparent affinity of the PCP binding site by high concentrations of NMDA. This may suggest an allosteric link between the PCP-sigma receptor and the NMDA-type glutamate-aspartate receptor. The receptors mediating excitatory amino acid-induced DA release were somewhat less selective than those on cholinergic neurons in their sensitivity to both Mg++ and PCP. Structure-activity-relationship studies suggested that the inhibition of ACh and DA release evoked by NMDA involves binding to the PCP-sigma receptor. Thus, the PCP-sigma receptor and the NMDA-preferring receptor both may modulate a Mg++-sensitive ionic conductance channel in an opposing manner.

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