title: Differential neuronal vulnerability to amino-oxyacetate and quinolinate in the rat parahippocampal region.
abstract: Injection of the "indirect" excitotoxin amino-oxyacetate into the entorhinal area causes acute behavioral seizures and preferential neuronal loss in layer III of the medial entorhinal cortex in rats. We examined here whether the effects of amino-oxyacetate could be duplicated by local injections of the endogenous N-methyl-D-aspartate receptor agonist and direct excitotoxin, quinolinate. Amino-oxyacetate (685 nmol) or quinolinate (30, 45 or 60 nmol) were injected into the entorhinal cortex of rats anesthetized with choral hydrate (360 mg/kg). Separate groups of animals were co-treated with the N-methyl-D-aspartate receptor antagonist dizocilpine maleate (2 mg/kg) or given a higher dose of chloral hydrate (500 mg/kg). Rats that received amino-oxyacetate and a low anesthetic dose consistently displayed acute behavioral seizures and showed preferential loss of neurons in layer III of the medial entorhinal cortex. Animals that were given quinolinate did not display behavioral seizures, and showed preferential degeneration of neurons in layer V of the entorhinal cortex. Moreover, quinolinate-injected rats frequently exhibited neuronal loss in the superficial layers of the dorsal perirhinal cortex. The behavioral and neuropathological sequelae of amino-oxyacetate, but not quinolinate-induced neurotoxicity, were abolished by prolonged chloral hydrate anesthesia. In spite of these apparent qualitative differences between the two toxins, neurodegeneration induced by either amino-oxyacetate or quinolinate was completely prevented by dizocilpine maleate. These data suggest that a heterogeneous distribution of pharmacologically distinct N-methyl-D-aspartate receptor subtypes in the parahippocampal region may underlie the distinct neurodegenerative properties of the two toxins. Since the lesion caused by amino-oxyacetate bears remarkable similarities to neuropathological changes which have been described in this structure in temporal lobe epilepsy, further elucidation of the mechanisms of cellular toxicity of amino-oxyacetate may hold clues for the pathogenesis of this disease.
authors.affiliation: Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore 21228, USA.
authors.forename: T
authors.initials: T
authors.lastname: Eid
authors.forename: F
authors.initials: F
authors.lastname: Du
authors.forename: R
authors.initials: R
authors.lastname: Schwarcz
mesh_terms: D000625:Aminooxyacetic Acid / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D016291:Dizocilpine Maleate / Q000494:pharmacology; D018728:Entorhinal Cortex / Q000033:anatomy & histology / Q000166:cytology / Q000187:drug effects; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D018682:GABA Agents / Q000008:administration & dosage / Q000494:pharmacology*; D006624:Hippocampus / Q000033:anatomy & histology / Q000166:cytology* / Q000187:drug effects; D007267:Injections; D008297:Male; D009474:Neurons / Q000187:drug effects*; D017378:Quinolinic Acid / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists
chemical_list: D018691:Excitatory Amino Acid Antagonists; D018682:GABA Agents; D016194:Receptors, N-Methyl-D-Aspartate; D000625:Aminooxyacetic Acid; D016291:Dizocilpine Maleate; D017378:Quinolinic Acid