BRAIN FOS INDUCTION IS A SENSITIVE BIOMARKER FOR THE LOWEST OBSERVED NEUROEXCITATORY EFFECTS OF DOMOIC ACID

Domoic acid induces Fos in several brain regions controlling memory pr ocessing and gastrointestinal functions. Pn the present study, we dete rmined serum levels of domoic acid that caused observable effects, and examined whether brain c-Sos was a sensitive marker for the lowest ob served neuroexcitatory effects in mice. Five different doses (0.25 to 4.0 mg/kg) of domoic acid were intraperitoneally administered Co mice, and the serum concentration of domoic acid was monitored using a radi oreceptor assay. The earliest neuroexcitatory effect of domoic acid on behavior was observed in the form of hyperactivity which occurred at 0.5 mg/kg (0.076 +/- 0.02 mu g/ml serum domoic acid, mean +/- SE, n = 5). However, stereotypic behavior (scratching) was observed only at do ses greater than or equal to 1.0 mg/kg (0.25 +/- 0.02 mu g/ml). At 2.0 mg/kg (0.54 +/- 0.04 mu g/ml) and higher, convulsions and seizures oc curred. Domoic acid induction of c-fos mRNA was detected in the whole brain at 1.0 mg/kg, whereas increased Fos immunostaining was localized in the dentate granule cells and the pyramidal cells of hippocampal f ormation at doses as low as 0.5 mg/kg (0.076 +/- 0.02 mu g/ml). Our re sults indicate that Fos expression in the hippocampus is a sensitive b iomarker for the neuroexcitatory effects of domoic acid, being induced at doses of domoic acid lower than those that elicit stereotypic beha vior. (C) 1996 Society of Toxicology.