DISSOCIATION BETWEEN THE EXCITATORY AND EXCITOTOXIC EFFECTS OF QUINOLINIC ACID ANALOGS ON THE STRIATAL CHOLINERGIC INTERNEURON

  • 1 January 1985
    • journal article
    • research article
    • Vol. 232  (3) , 873-882
Abstract
Analogs of quinolinic acid were tested in rats for excitatory properties in evoking neurotransmitter release from striatal cholinergic interneurons and for their ability to lesion these same neurons in vivo (excitotoxin activity). The ability of these analogs to inhibit the specific binding of several ligands thought to label excitatory amino acid receptors was also investigated. Dipicolinic acid (2,6-pyridine dicarboxylic acid) was found to be as potent and as efficacious as quinolinic acid (2,3-pyridine dicarboxylic acid) at N-methyl-D-aspartate (NMDA)-type receptors mediating [3H]acetylcholine release from striatal slices. Unlike quinolinate, the structure of NMDA is not superimposable upon that of dipicolinic acid. Unlike quinolinic acid, dipicolinic acid injected intrastriatally did not produce detectable excitotoxic lesions. Phthalic acid (1,2-benzene dicarboxylic acid), which lacks a N2, also evoked [3H]acetylcholine release from striatal slices, apparently by acting at NMDA-type receptors. Phthalic acid was equipotent to quinolinic acid and dipicolinic acid but possessed less intrinsic activity than those compounds in evoking [3H]acetylcholine release. Despite its lack of a N2 and low intrinsic activity, intrastriatal injection of phthalic acid produced axon-sparing lesions of intrinsic cell bodies, like quinolinic acid as assessed by neurochemical and histologic methods. Quinolinic acid, dipicolinic acid and phthalic acid were moderately potent inhibitors (Ki .simeq. 100 .mu.M) of the specific binding of 2-[3H]amino-7-phosphonoheptanoic acid a compound thought to be a competitive antagonist of NMDA-type receptors. These 3 compounds failed to inhibit the chloride-dependent or chloride-independent binding of L-[3H]glutamate or [3H]kainic acid. A major dissociation between the structure-activity relationships for excitotoxicity vis-a-vis excitation as reflected in the [3H]acetylcholine release model, for compounds acting at NMDA-type receptors is suggested.