DOMOIC ACID-TREATED CYNOMOLGUS MONKEYS (MACACA-FASCICULARIS) - EFFECTS OF DOSE ON HIPPOCAMPAL NEURONAL AND TERMINAL DEGENERATION

Domoic acid is a tricarboxylic amino acid (structurally related to kai nic acid and glutamic acid) that is found in the environment as a cont aminant of some seafood. To determine the nature of any neurological d amage caused by domoate, as well as the minimum neurotoxic dose, juven ile and adult monkeys were dosed intravenously with domoate at one of a range of doses from 0.25 to 4 mg/kg. When animals were perfused one week later, histochemical staining using a silver method to reveal deg enerating axons and cell bodies showed two distinct types of hippocamp al lesions. One lesion, termed 'Type A', was a small focal area of sil ver grains restricted to CA2 stratum lucidum, the site of greatest kai nic acid receptor concentration in the brain. Type A lesions occurred over a dose range of 0.5 to 2.0 mg/kg in juvenile animals and 0.5 to 1 .0 mg/kg in adult animals. No mortality occurred in any of the juvenil e monkeys, but one juvenile animal that received 4.0 mg/kg sustained a second type of lesion, termed 'Type B', characterized by widespread d amage to pyramidal neurons and axon terminals of CA4, CA3, CA2, CA1, a nd subiculum subfields of the hippocampus. Doses of more than 1.0 mg/k g in the adult monkeys either proved lethal or resulted in Type B lesi ons. Induction of c-fos protein had occurred in the hippocampal dentat e gyrus and CA1 regions of moribund animals perfused within hours of t heir initial dose. Our results show that relatively low doses of domoi c acid selectively effect mossy fiber terminals, that larger (near let hal) doses damage hippocampal pyramidal neurons and their axons, that some moribund monkeys had experienced limbic seizures prior to death, and that adult animals are more sensitive to domoic acid than juvenile s.