Effects of the NMDA receptor antagonist D-CPPene on extracellular levels of dopamine and dopamine and serotonin metabolites in striatum of kindled and non-kindled rats

Electrical kindling in rats has previously been shown to cause a hypersensi tivity to amphetamine-like behavioral effects of competitive NMDA receptor antagonists such as D,L-(E)-amino-4-methyl-5-phosphono-3-pentenoic acid (CG P 37849), D-(E)-2-amino-3-methy-5phosphono-3-pentenoic acid (CGP 40116), or 3-(2-carboxypiperazine-4-yl)propenyl-1-phosphonate (SDZ EAA 494: D-CPPene) . From this observation, it was concluded that kindling-induced epileptogen esis enhances the potential of competitive NMDA receptor antagonists to ind uce such unwanted adverse effects, predicting that such drugs may induce mo re severe side effects in epileptic patients than in healthy volunteers, wh ich was confirmed in clinical trials. In the present study, we thought to e xamine the biochemical basis for the enhanced susceptibility of kindled rat s to amphetamine-like behavioral effects of NMDA receptor antagonists by me asuring extracellular levels of dopamine, the dopamine metabolites dihydrox yphenylacetic acid (DOPAC) and homovanillic acid (HVA), and the serotonin ( 5-hydroxytryptamine, 5-HT) metabolite 5-hydroxyindoleacetic acid (5-HIAA) i n the striatum of awake, behaving rats, using in vivo microdialysis. When a dministered systemically, D-CPPene, 15 mg/kg i.p., caused more intense ster eotyped behaviors in kindled than in non-kindled mts. While there was no si gnificant alteration in extracellular dopamine, in both groups of rats HVA and 5-HIAA significantly increased. In kindled rats, basal levels of HVA an d the increase in HVA in response to d-CPPene were higher compared to non-k indled animals. When administered intrastriatally via the microdialysis pro be: D-CPPene, 10 mu M, significantly increased dopamine, HVA and 5-HIAA, wh ich was associated with stereotyped behaviors. Again, these behaviors were more intense in kindled rats. The data indicate that a competitive NMDA rec eptor antagonist at high. behaviorally active doses induces increases in st riatal dopamine and presumably also 5-HT release, which most likely underli e the amphetamine-like behavioral effects of such a drug. Kindling enhances the sensitivity to these behavioral effects, which could be related to a m ore marked dopamine and 5-HT release. Thus, in order to avoid false predict ions for the clinical situation, it is important to study the behavioral an d biochemical effects of NMDA receptor antagonists not only in naive, healt hy animals but also in animals that mimic the disease for winch a drug is d eveloped. (C) 1999 Elsevier Science B.V. All rights reserved.