Cerebral ischemia decreases the behavioral effects and mortality rate elicited by activation of nmda receptors in mice

Abstract

The purpose of this study was to determine whether prior transient cerebral ischemia, in conscious mice, would alter the biological responses resulting from excessive activation of N- methyl- d-aspartate (NMDA) receptors, in an early stage. The responses to the activation of NMDA receptors by an intracerebroventricular injection of NMDA, such as wild running, tonic and clonic convulsions, absence of the visual placing reflex, loss of the righting reflex, impaired motor function and a high mortality rate, were to a large extent prevented if 30 min before treatment, either a 10-min period of global cerebral ischemia was induced or a 1 nmol intraventricular injection of NMDA was given but not if either of the above procedures was done one day before the test dose of NMDA. In contrast, behavioral symptoms, in response to activation of non-NMDA-type glutamate receptors elicited by intraventricular injection of either kainic acid or AMPA, were not clearly affected. Transient systemic hypercapnic anoxia (22-sec exposure to 100% CO 2 gas), before treatment with NMDA did not significantly reduce the NMDA-induced behavior. The severity of these behavioral responses and high mortality rate observed after intraventricular injection of pentylenetetrazole (PTZ, 30 μmol) were not altered by either prior global ischemie insult or by a preexposure to NMDA given intraventricularly. The NMDA antagonist, MK801 (0.1 and 0.3 mg/kg i.p.) greatly reduced the behavioral effects and mortality rate, resulting from the intraventricular injection of NMDA and somewhat reduced the effects of the intraventricular injection of PTZ. The reduced response to NMDA, following a prior activation of NMDA receptors through either injection of NMDA or transient cerebral ischemia, may be due to a decreased number of NMDA receptors or sensitivity and/or to depression of pathways in the NMDA receptor-mediated biochemical cascade. The physiological significance of this finding lies in the implication that repeated strong activation of NMDA receptors, within a short period, results in a diminution of the NMDA-induced behavioral effect, and mortality rate, in very early stage.