Neonatal exposure to D,L-2-amino-3-phosphonopropionate (D,L-AP3) produces lesions in the eye and optic nerve of adult rats.
Metabotropic glutamate receptors are a recently described receptor class with emerging importance in synaptic plasticity and brain development. Activation of metabotropic glutamate receptors results in several cellular secondary messenger events that are especially important during postnatal development. This study characterized the effects of D,L-2-amino-3-phosphonopropionate (D,L-AP3), an aspartic acid analog with agonist and antagonist activity at the metabotropic receptor, on the postnatal development of the rat eye and optic nerve. Sprague-Dawley rat pups were treated daily (i.p.) with saline or 500 mg/kg D,L-AP3 on postnatal days (PND) 4-10 or 10-14. After making clinical and ophthalmoscopic examinations, rats were necropsied between 65 and 70 days of age and light microscopic evaluations were made of eyes and optic nerves. Between postnatal days 10-20, all treated rats exhibited motor tremors, circling, and head tilt. Ophthalmoscopic lesions were more severe in rats treated on days 4-10 than days 10-14 and included decreased retinal vasculature, cataracts, and retinal dysplasia, hypoplasia, and detachment. All rats treated on days 4-10 had severe optic nerve atrophy/hypoplasia grossly and severe retinal atrophy, retinal detachment, and cataracts histologically. Seven of eight rats treated on days 10-14 had qualitatively similar but less severe lesions. Overall, rats treated with D,L-AP3 on PND 4-10 had earlier and more severe retinal and optic nerve lesions when compared to rats treated on PND 10-14. These data characterize the morphologic effects in adult rats exposed to D,L-AP3 as neonates and suggest a possible role for the metabotropic receptor in the postnatal development of retina and optic nerve.
Fix
A S
AS
Toxicology Research Laboratories, Lilly Research Laboratories, Eli Lilly and Company, Greenfield, IN 46140.
Schoepp
D D
DD
Olney
J W
JW
Vestre
W A
WA
Griffey
K I
KI
Johnson
J A
JA
Tizzano
J P
JP
D000375:Aging / Q000502:physiology; D000409:Alanine / Q000031:analogs & derivatives* / Q000633:toxicity; D000818:Animals; D000831:Animals, Newborn / Q000502:physiology*; D001522:Behavior, Animal / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D005123:Eye / Q000473:pathology; D005128:Eye Diseases / Q000139:chemically induced* / Q000473:pathology; D008297:Male; D009900:Optic Nerve / Q000473:pathology; D009901:Optic Nerve Diseases / Q000139:chemically induced* / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000187:drug effects; D012164:Retinal Diseases / Q000139:chemically induced / Q000473:pathology
D018094:Receptors, Metabotropic Glutamate; C000211:2-amino-3-phosphonopropionic acid; D000409:Alanine