AbstractWe previously found that quinolinic acid striatal excitotoxin lesions result in a relative sparing of somatostatin and neuropeptide Y neurons. In the present study we examined dose‐response effects of excitotoxins acting at the three subtypes of glutamate receptors: N‐methyl‐D‐aspartate (AA1), quisqualate (AA2), and kainic acid (AA3). Concentrations of both somatostatin‐like immunoreactivity (SLI) and neuropeptide a Y‐like immunoreactivity (NPYLI) were compared with those of substance P‐like immunoreactivity (SPLI) and GABA. Kainic acid (AA3), quisqualic acid (AA2), and AMPA (AA2) resulted in dose‐dependent reductions in all four neurochemical markers examined, while N‐methyl‐D,L‐aspartate (AA1) and quinolinic acid (AA1) resulted in relative sparing of SLI and NPYLI. At doses of each excitotoxin which resulted in comparable 50% reductions in both GABA and SPLI only N‐methyl‐D,L‐aspartate and quinolinic acid had no significant effect on concentrations of SLI and NPYLI. The relative sparing of somatostatin‐neuropeptide Y neurons was confirmed histologically by using histochemical staining for NADPH‐diaphorase neurons combined with either Nissl stains, or immunohistochemical staining for enkephalin. Lessions with N‐methyl‐D‐aspartate agonists resulted in preferential sparing of NADPH‐diaphorase neurons while these neurons were more vulnerable than other neurons to kainic acid or AMPA. Choline acetyltransferase neurons were relatively spared, as compared with other neurons, by agents acting at all three glutamate receptor subtypes. N‐methyl‐D,L‐aspartate lesions were blocked with MK‐801, while there was no effect on quisqualic acid or kainic acid lesions. The relative sparing of somatostatin‐neuropeptide Y neurons following striatal excitotoxin lesions with N‐methyl‐D‐aspartate (AA1) agonists probably reflects a paucity of AA1 receptors on these neurons. Since these neurons are also spared in Huntington's disease, excitotoxins acting at the N‐methyl‐D‐aspartate (AA1)