Excitatory amino acid (EAA)-induced cell death in the striatum is dependent upon intact glutamatergic afferents arising from the cerebral cortex. Through a mechanism possibly related to inhibition of glutamate release, adenosine receptor agonists attenuate EAA induced toxicity in the rat striatum. In the present study, we examined whether 2-chloroadenosine (2CLA), a stable adenosine analog, protects against toxicity induced by kainate (KA), quisqualate (QUIS), N-methyl-D-aspartate (NMDA), and ibotenate (IBO). In vivo intrastriatal injections of 2CLA (50 nmol) with each EAA tested provided a partial but significant protective effect versus injection of the EAA alone, as measured by striatal concentrations of gamma-aminobutyric acid (GABA) and substance P-like immunoreactivity (SP-LI). These results show that 2CLA attenuates both NMDA- and non-NMDA-mediated neuronal cell death.