Kainic acid (KA) induces selective neuronal damage in the CA3 pyramidal neurons of rat hippocampus. However, the mechanism of this selective neuronal vulnerability remains unclear. In this study, we examined the contribution of endogenous adenosine, a potent inhibitory neuromodulator, to the differences in the neuronal vulnerability of the hippocampus. Pretreatment with 8-cyclopenthyltheophylline (CPT), an A1 adenosine receptor antagonist, significantly exacerbated KA-induced neuronal cell loss in both the CA1 and the CA3. Although c-Jun phosphorylation, a critical step in neuronal apoptosis, was not detected in the vehicle-injected rat hippocampus, c-Jun phosphorylation was induced in the CA3 by the injection of KA alone. Pretreatment with CPT induced c-Jun phosphorylation in both the CA1 and the CA3. MHC class II antigen, a marker for activated microglia, was also detected in the regions of c-Jun phosphorylation. Coadministration of N6-cyclopenthyladenosine (CHA), an A1 adenosine receptor agonist, attenuated the neuronal cell loss in the CA1 and the CA3 with or without pretreatment with CPT. These results strongly suggest that endogenous adenosine has neuroprotective effects against excitotoxin-induced neurodegeneration in the CA1 thorough its A1 receptors.