PROGRESSIVE RETINAL TOXICITY IN NEONATAL RATS TREATED WITH D,L-2-AMINO-3-PHOSPHONOPROPIONATE (D,L-AP3)

D,L-2-amino-3-phosphonopropionate (D,L-AP3) has complex pharmacologic activity at central nervous system metabotropic glutamate receptors im portant in excitatory neurotransmission and development. Previous stud ies have described retinal and optic nerve atrophy in adult rats after postnatal treatment with D,L-AP3. Using neonatal male Sprague-Dawley rats, the present studies examined normal postnatal retinal developmen t (n = 20) and the progression of retinal toxicity induced by D,L-AP3 (n = 30). Retinal development was examined by light microscopy on post natal days (PNDs) 5, 9, 12, 16, and 22. Between PNDs 5 and 16, the ret ina underwent considerable postnatal differentiation. A prominent neur oblastic layer evident on PND 5 differentiated into outer retinal laye rs by PND 16. To examine the effects of D,L-AP3, neonatal rats were tr eated intraperitoneally with sterile water or 400 mg/kg/day D,L-AP3 On PNDs 3-6. On PNDs 5, 7, 10, 15, and 20, retinas were examined by ligh t and electron microscopy. On PNDs 5 and 7, cells with swollen, pale c ytoplasm were evident in the more differentiated inner nuclear layer a nd in the middle of the developing neuroblastic layer. Retinal toxicit y rapidly progressed after treatment, because developing outer retinal layers had cytoplasmic swelling, nuclear pyknosis, and necrosis on PN D 10. By PNDs 15 and 20, retinal dystrophy was severe and involved pri marily outer layers. This study showed that early postnatal treatment with D,L-AP3 initiates rapidly progressing retinal toxicity, thus impl icating metabotropic glutamate receptors in the postnatal retinal deve lopment of rats.