The peripheral benzodiazepine receptor is a sensitive indicator of domoic acid neurotoxicity.
To evaluate the utility of the peripheral benzodiazepine receptor (PBR) as a biomarker of neurotoxicity, we measured receptor levels after sub-seizure doses of domoic acid (0-3.0 mg/kg) in rats using [3H]PK-11195 autoradiography. PBR expression in limbic structures was significantly increased 5 days, but not 24 or 48 h after injection of 3.0 mg/kg domoic acid. The largest increase in [3H]PK-11195 binding (> 500% above control) was found in the CA3 subfield of the hippocampus. Other limbic structures including the CA1 hippocampal subfield, subiculum, dentate gyrus and amygdala also showed significant increases in PBR expression, as did the striatum and substantia nigra pars reticulata. Smaller but significant increases were also observed 5 days after injection of 1.5 mg/kg, but not in animals treated with 0.75 mg/kg domoic acid. No pathology was observed after routine histological staining of brain tissue. Spatial learning and memory, a process thought to be associated with the hippocampus, was assessed in the Morris water maze. Groups treated with 1.5 and 3.0 mg/kg, but not 0.75 mg/kg domoic acid were significantly impaired in water maze performance. These findings suggest that the PBR could provide a sensitive and specific biomarker of neurotoxicity.
Kuhlmann
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Department of Environmental Health Sciences, Johns Hopkins University, School of Hygiene and Public Health, Baltimore, MD 21205, USA.
Guilarte
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D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000378:metabolism*; D007546:Isoquinolines / Q000378:metabolism; D007608:Kainic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D009043:Motor Activity / Q000187:drug effects; D009498:Neurotoxins / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D011963:Receptors, GABA-A / Q000378:metabolism*; D014018:Tissue Distribution
D007546:Isoquinolines; D009498:Neurotoxins; D011963:Receptors, GABA-A; C012301:domoic acid; D007608:Kainic Acid; C037850:PK 11195