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.