ELECTRICAL BUT NOT CHEMICAL KINDLING INCREASES SENSITIVITY TO SOME PHENCYCLIDINE-LIKE BEHAVIORAL-EFFECTS INDUCED BY THE COMPETITIVE NMDA RECEPTOR ANTAGONIST D-CPPENE IN RATS

We have previously reported that a competitive N-methyl-D-aspartate (N MDA) receptor antagonist, DL-[E]-2-amino-4-methyl-5-phosphono-3-penten oic acid (CGP 37849), produces stereotyped behaviors and hyperlocomoti on in amygdala kindled rats at doses which do not induce such phencycl idine (PCP)-like behaviors in nonkindled rats, indicating that kindlin g predisposes rats to such adverse effects of competitive NMDA recepto r antagonists. From these data we predicted that epileptic patients ma y exhibit a hypersensitivity to PCP-like adverse effects of competitiv e NMDA receptor antagonists, which was subsequently confirmed in a cli nical trial with D-CPPene (SDZ EAA-494; (2-carboxypiperazine-4-yl)prop enyl-1-phosphonate). For further exploration of the functional alterat ions in NMDA receptor responsiveness produced by kindling, we studied whether the enhanced susceptibility of amygdala-kindled rats to PCP-li ke adverse effects of CGP 37849 is also observed with D-CPPene, Furthe rmore, we determined whether the enhanced susceptibility of kindled ra ts to such adverse effects occurs only after relatively short interval s following the last seizure, as used in our previous study, or is a m ore permanent phenomenon. For this purpose, we compared adverse effect s in kindled rats not only with naive (non-implanted) controls, as don e in our previous study, but used electrode-implanted nonkindled rats as an additional control to assess the possible bias of mere electrode -implantation. In addition, we studied whether the enhanced susceptibi lity to NMDA receptor antagonists of electrically kindled rats is also present in chemically kindled animals. In some experiments, the PCP-l ike uncompetitive NMDA receptor antagonist MK-801 (dizocilpine) was in cluded for comparison. In amygdala kindled rats, D-CPPene produced sig nificantly more stereotyped behaviors than in electrode-implanted or n aive nonkindled controls. The enhanced sensitivity of electrically kin dled rats to PCP-like stereotypies induced by D-CPPene was observed bo th 7 and 180 days after the last kindled seizure, indicating a long-la sting if not permanent hypersensitivity to these adverse effects. In a ddition, more intense circling was observed in amygdala kindled rats, whereas hyperlocomotion only tended to be more intense after D-CPPene in kindled rats. These alterations in D-CPPene-induced behaviors were not observed after chemical kindling with pentylenetetrazole, but D-CP Pene induced significantly less hypothermia in chemically kindled rats both 7 and 70 days after the last seizure. The data demonstrate that kindling produces long-lasting alterations in some adverse effects of D-CPPene, substantiating that epileptogenesis as initiated by kindling renders the brain more susceptible to PCP-like behavioral side effect s of competitive NMDA receptor antagonists. (C) 1998 Elsevier Science B.V. All rights reserved.