Several N-methyl-D-aspartate (N M D A) receptor antagonists are being developed to reduce overstimulation of N M D A receptors by excessive glutamate, released as a consequence of acute cerebral hypoxial ischemia after stroke or head trauma. N M D A receptor antagonists, including Selfotel (C G S 19755), have been demonstrated to cause neuronal vacuolation and neuronal necrosis in the retrosplenial and / or posterior cingulate cerebral cortices of rats; however, little in formation is available on their effects on the cerebral cortices of primates. Cynomolgus monkeys were treated with single parenteral doses of N M D A antagonists (Selfotel or M K-801). Monkeys were administered intravenous doses of Selfotel at 2 or 20 mg/kg and were necropsied 4, 24, or 72 h postdose. Additional monkeys, administered M K-801 subcutaneously at 0.25 mg/kg, were necropsied 4 or 72 h postdose. Overt, centrally mediated clinical signs occurred in both Selfote l- and M K-801–treated monkeys (e.g., at axia, hypoactivity, salivation, convulsions, disorientation, dyspnea, apnea, recumbency, and cyanosis). Brains were perfusion-fixed in situ with 1% paraformaldehyde and 1.5% glutaraldehyde in pyrophosphate buffer. Brain sections from the animals necropsied 4 and 24 h postdose we reembedded in plastics (Durcupan) and paraffin, cut at 1 or 2 μm thickness, and stained with Richardson's stain. Brains from the animals necropsie d 72 h postdose were embedded in paraffin, cut at 4 μm, and stained with hematoxylin and eosin. Microscopic examination of posterior cingulate and/or retrosplenial cerebral cortices from monkey streated with Selfotel or M K-801 did not reveal any neuronal vacuolation or necrosis.
Competitive and uncompetitiveN-methyl-d-aspartate antagonist discriminations in pigeons: CGS 19755 and phencyclidine