Somatostatin (SST) is a multifunctional peptide and involves in several neurodegenerative diseases. N-Methyl-D-asparate (NMDA) receptor agonist quinolinic acid (QUIN)-induced neurotoxicity mimics an experimental model of Huntington's disease that is characterized by the selective preservation of medium-sized aspiny interneurons and degeneration of medium-sized spiny projection neurons in striatum. In QUIN- and NMDA-induced neurotoxicity, increased expression of SST and messenger RNA levels along with SST release in culture medium is generally observed. However, the molecular mechanisms and the functional consequences of increased SST are still obscure. In the present study, the role of SST was determined using immunoneutralization and immunoblockade of SST in cultured striatal neurons upon QUIN- and NMDA-induced neurotoxicity. The immunoblockade of SST with antisense oligonucleotides and immunoabsorption of released SST with specific antibodies potentiate QUIN- and NMDA-induced neuronal cell death. NADPH-diaphorase positive neurons that are selectively spared in several processes of neurodegeneration result in severe damage upon immunoblockade or immunoabsorption of SST. In addition, exogenous SST along with QUIN and NMDA provides selective preservation of projection neurons, which are selectively susceptible in excitotoxicity. Neuroprotective effect of SST is completely blocked by pertussis toxins, suggesting the role of somatostatin receptors. Taken together, these results provide first evidence that the presence of SST is a unique feature for the selective sparing of medium sized aspiny interneurons in excitotoxicity.