In a recent study, we employed an in vivo model of retinal excitotoxicity to investigate the neuroprotective effect of somatostatinergic agents. Intravitreal administration of somatostatin and sst(2) selective agonists protected the retina from (RS)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid hydrobromide (AMPA) induced excitotoxicity. The sst(1) and sst(4) selective ligands had no effect (Kiagiadaki and Thermos, 2008). The presence of sst(5) receptors in rat retina was only recently reported (Ke and Zhong, 2007). Synthetic agonists that activate sst(2) receptors also bind with high affinity to the sst(5) subtype. In the present study the putative neuroprotective effects of sst(5) receptor activation were investigated. Adult female and male Sprague-Dawley (250-350g) rats were employed. Groups of animals received intravitreally PBS (50mM) or AMPA (42 nmol/eye) alone or in combination with L-817,818 (sst(5), 10(-5), 10(-4)M). To exclude neuroprotective effects via the activation of sst(2) receptors, L-817,818 (10(-4)M) was coinjected with the sst(2) antagonist CYN-154806 (10(-4)M). Immunohistochemistry (IHC) studies using the anti-retinal marker choline acetyltransferase (ChAT) and TUNEL staining were employed to examine retinal cell loss and protection. IHC and Western blot analysis were also employed to assess whether the sst(5) receptors are viable in the AMPA treated tissue as compared to control retina. sst(5) receptors were not affected by AMPA. L-817,818 protected the retina from the AMPA insult in the dose of 10(-4)M, while CYN-154806 (10(-4)M) had no effect on the sst(5) neuroprotection. TUNEL staining confirmed the AMPA-induced retinal toxicity and the L-817,818 neuroprotection. These results demonstrate for the first time that sst(5) receptors are functional in the retina, and that sst(5) analogs administered intravitreally protect the retina from excitotoxicity. Further studies are essential to ascertain the therapeutic relevance of these results.