Enkephalinergic striatal projection neurons become less affected by quinolinic acid than substance P-containing striatal projection neurons as rats age.

While the excitotoxic vulnerability of striatal neurons is known to be greater in juvenile than adult animals, it is uncertain if striatal neuron types decline differentially in their vulnerability with age. To examine this issue, we unilaterally injected quinolinic acid (QA), an N-methyl-d-aspartate (NMDA) receptor agonist, into the striatum of juvenile and adult rats, and used in situ hybridization histochemistry with oligonucleotide probes for preproenkephalin and preprotachykinin mRNA to label surviving enkephalinergic (ENK) and substance P-containing (SP) neurons in adjacent sections through the injection center. The results confirmed that the region of severe damage is greater in young than adult animals, but revealed that at the very center of the QA injection, labeled neuron abundance was lower in adult than juvenile striatum. In juvenile rats, the vulnerability of the ENK neurons at all distances from the injection center was the same as that of the SP neurons. By contrast, in adult rats, the ENK neuron survival was greater than the SP neuron survival at all distances beyond the lesion center. The SP neuron survival outside the injection center in the adult rats was similar to that in juvenile rats, while the ENK neuron survival beyond the injection center was better in adult than juvenile rats. These data indicate that there is an age-dependent decrease in the vulnerability of ENK but not SP striatal projection neurons to QA-mediated injury in rats. The results also raise the possibility that, if an excitotoxic process is involved in HD pathogenesis, a differential age-related decline in the sensitivity of striatal projection neuron types to this process may contribute to the more uniform striatal neuron loss in juvenile-onset Huntington's disease (HD) and the more differential loss in adult-onset HD.