FOCAL ISCHEMIA ENHANCES THE ADVERSE EFFECT POTENTIAL OF N-METHYL-D-ASPARTATE RECEPTOR ANTAGONISTS IN RATS

Recent clinical trials with non-competitive and competitive N-methyl-D -aspartate (NMDA) receptor antagonists in patients with stroke have sh own that these patients develop more adverse effects, particularly psy chomimetic effects such as hallucinations and agitation, than normal v olunteers at equivalent doses. We therefore examined whether such incr eased adverse effect potential of NMDA antagonists also occurs in a ra t model of permanent focal ischemia. For this purpose, the right middl e cerebral artery was occluded under halothane anesthesia, and behavio ral alterations in response to the non-competitive NMDA antagonist, MK -801 (dizocilpine), were recorded after recovery from anesthesia. Beha vioral alterations in ischemic rats were compared with those in sham-l esioned rats in a blinded fashion. MK-801 (0.4 mg/kg) induced psychomi metic-like stereotyped behaviors which were about twice as intense in ischemic than in non-ischemic rats. A similar trend for enhanced adver se effects was seen with the competitive NMDA antagonist CGS 19755 (Se lfotel). Although more NMDA antagonists have to be tested to draw defi nite conclusions, the present data may indicate that enhanced sensitiv ity of stroke patients to adverse effects of NMDA antagonists can be p redicted by use of a focal ischemia model in rats, thus allowing use o f this model for developing novel cytoprotective strategies targeted t o minimize glutamatergic excitotoxicity with reduced adverse effect po tential. (C) 1998 Elsevier Science Ireland Ltd.