Domoic acid acts at both kainic acid (KA) and a-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA)-sensitive glutamate receptors and induces tolerance against subsequent domoic acid insult in young but not aged rat hippocampus. To determine the receptor specificity of this effect, tolerance induction was examined in hippocampal slices from young and aged rats. Slices were preconditioned by exposure to low-dose KA to activate kainate receptors, or the AMPAreceptor selective agonist (S)-5-fluorowillardiine (FW), and following washout, tolerance induction was assessed by administration of high concentrations of KA or FW (respectively). FW preconditioning failed to induce tolerance to subsequent FW challenges, while KA-preconditioned slices were significantly resistant to the effects of high-dose KA. KA preconditioning failed to induce tolerance in aged CA1. Given the lasting nature of the tolerance effect, we examined Gprotein-coupled receptor function. A number of ionotropic KA receptor agonists and antagonists significantly reduced constitutive GTPase activity in hippocampal membranes from young but not aged rats. Furthermore, in young CA1, low concentrations of the AMPA/KA blocker GYKI-52466 also induced tolerance to high-dose KA. Our findings suggest that tolerance is triggered by a selective reduction in constitutive KA-sensitive G-protein activity, and that this potential neuroprotective mechanism is lost with age.