NEURONAL VACUOLE FORMATION IN THE RAT POSTERIOR CINGULATE RETROSPLENIAL CORTEX AFTER TREATMENT WITH THE N-METHYL-D-ASPARTATE (NMDA) ANTAGONIST MK-801 (DIZOCILPINE MALEATE)

Cytoplasmic vacuoles appear in neurons of the posterior cingulate/retr osplenial cortex (PC/RS) of rats after treatment with N-methyl-D-aspar tate (NMDA) receptor antagonists. Prominent dilatation of mitochondria and endoplasmic reticulum has been described within 2 h; however, the ultrastructural features of vacuole formation are unknown. To investi gate this, the present study examined the PC/RS cortex of male rats (a ge 60-70 days) at 15, 30, 45, 60, 90, and 120 min after subcutaneous t reatment with 1 mg/kg of the noncompetitive NMDA antagonist MK-801 (di zocilpine maleate, 5-methyl-10, 11-dihydro-5H-dibenzo [a,d] cyclohepte n-5,10-imine). Subtle mitochondrial dilatation was identified in a few neurons as early as 15 min postdose (MPD). By 30 MPD, dilatation was more pronounced in mitochondria and also involved the endoplasmic reti culum and perinuclear space. Ribosomal disaggregation and degranulatio n were also evident by 30 MPD. At all subsequent time points, dilatati on of mitochondria and endoplasmic reticulum progressed in severity. A lthough the relative involvement of mitochondria and endoplasmic retic ulum varied, glia were not involved. These ultrastructural data sugges t that after treatment with MK-801, mitochondrial dilatation precedes involvement of endoplasmic reticulum in vacuolization of susceptible P C/RS cortical neurons. The early mitochondrial effects identified in t his study suggest an initial metabolic insult that rapidly progresses to affect endoplasmic reticulum and ribosomes. This strengthens the re lationship between the ability of certain NMDA antagonists to induce e nergy perturbations and neuronal vacuoles in the same region of the ra t cerebral cortex.