Domoic acid preconditioning and seizure induction in young and aged rats

Abstract

Clinical reports suggest that the elderly are hypersensitive to the neurological effects of domoic acid (DOM). In the present study we assessed DOM-induced seizures in young and aged rats, and seizure attenuation following low-dose DOM pretreatment (i.e. preconditioning). Seizure behaviours following saline or DOM administration (0.5-2mg/kg i.p.) were continuously monitored for 2.5h in naïve and DOM preconditioned rats. Competitive ELISA was used to determine serum and brain DOM concentrations. Dose- and age-dependent increases in seizure activity were evident in response to DOM. Lower doses of DOM in young and aged rats promoted low level seizure behaviours. Animals administered high doses (2mg/kg in young; 1mg/kg in aged) progressed through various stages of stereotypical behaviour (e.g., head tics, scratching, wet dog shakes) before ultimately exhibiting tonic-clonic convulsions. Serum and brain DOM analysis indicated impaired renal clearance as contributory to increased DOM sensitivity in aged animals, and this was supported by seizure analysis following direct intrahippocampal administration of DOM. Preconditioning young and aged animals with low-dose DOM 45-90 min before high-dose DOM significantly reduced seizure intensity. We conclude that age-related supersensitivity to DOM is related to reduced clearance rather than increased neuronal sensitivity, and that preconditioning mechanisms underlying an inducible tolerance to excitotoxins are robustly expressed in both young and aged CNS.