Age-related changes in tolerance to the marine algal excitotoxin domoic acid.
During an incident of toxic mussel poisoning, the epileptogenic excitotoxin domoic acid (DOM) was associated with lasting neurological deficits mainly in older patients (), suggesting supersensitivity to excitotoxins is a feature of brain aging. Here, hippocampal slices from young (3 months) and aged (26-29 months) Sprague Dawley rats were assessed by CA1 field potential analysis before and after preconditioning with DOM. In naïve slices from young animals, DOM produced initial hyperexcitability followed by significant dose-dependent reductions in population spike amplitude during prolonged application. Following toxin washout, only small changes in neuronal activity were evident during a second application of DOM, suggesting that a resistance to the effects of DOM occurs in hippocampal slices which have undergone prior exposure to DOM. This inducible tolerance was not antagonized by the NMDA receptor blockers APV or MK-801, nor was it diminished by the group I, II or III mGluR blockers AIDA, CPPG and EGLU. Likewise, neither the AMPA/KA blocker CNQX nor the VSCC blocker nifedipine were effective in blocking tolerance induction in young slices. Field potential analysis revealed significant age-related reductions in CA1 EPSP strength, population spike amplitude and paired-pulse inhibition, but aged slices did not differ in sensitivity to DOM relative to young. However, aged CA1 failed to exhibit any tolerance to DOM following preconditioning, suggesting that a loss of inducible neuroprotective mechanisms may account for increased sensitivity to excitotoxins during aging.
Kerr
D Steven
DS
Department of Pharmacology and Toxicology, University of Otago School of Medical Sciences, Dunedin, New Zealand. steve.kerr@stonebow.otago.ac.n2
Razak
Asheema
A
Crawford
Nicola
N
D000375:Aging / Q000502:physiology*; D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology; D004361:Drug Tolerance; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology / Q000502:physiology; D066298:In Vitro Techniques; D007608:Kainic Acid / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000633:toxicity*; D008297:Male; D009467:Neuromuscular Depolarizing Agents / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D017470:Receptors, Glutamate / Q000187:drug effects
D002121:Calcium Channel Blockers; D018691:Excitatory Amino Acid Antagonists; D009467:Neuromuscular Depolarizing Agents; D017470:Receptors, Glutamate; C012301:domoic acid; D007608:Kainic Acid