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 hypersensitivity to amphetamine-like behavioral effects of competitive NMDA receptor antagonists such as D,L-(E)-amino-4-methyl-5-phosphono-3-pentenoic acid (CGP 37849), D-(E)-2-amino-4-methyl-5-phosphono-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 epileptogenesis enhances the potential of competitive NMDA receptor antagonists to induce such unwanted adverse effects, predicting that such drugs may induce more severe side effects in epileptic patients than in healthy volunteers, which was confirmed in clinical trials. In the present study, we thought to examine the biochemical basis for the enhanced susceptibility of kindled rats to amphetamine-like behavioral effects of NMDA receptor antagonists by measuring extracellular levels of dopamine, the dopamine metabolites dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), and the serotonin (5-hydroxytryptamine, 5-HT) metabolite 5-hydroxyindoleacetic acid (5-HIAA) in the striatum of awake, behaving rats, using in vivo microdialysis. When administered systemically, D-CPPene, 15 mg/kg i.p., caused more intense stereotyped behaviors in kindled than in non-kindled rats. While there was no significant alteration in extracellular dopamine, in both groups of rats HVA and 5-HIAA significantly increased. In kindled rats, basal levels of HVA and the increase in HVA in response to D-CPPene were higher compared to non-kindled animals. When administered intrastriatally via the microdialysis probe, D-CPPene, 10 microM, significantly increased dopamine, HVA and 5-HIAA, which was associated with stereotyped behaviors. Again, these behaviors were more intense in kindled rats. The data indicate that a competitive NMDA receptor antagonist at high, behaviorally active doses induces increases in striatal dopamine and presumably also 5-HT release, which most likely underlie the amphetamine-like behavioral effects of such a drug. Kindling enhances the sensitivity to these behavioral effects, which could be related to a more marked dopamine and 5-HT release. Thus, in order to avoid false predictions for the clinical situation, it is important to study the behavioral and biochemical effects of NMDA receptor antagonists not only in naive, healthy animals but also in animals that mimic the disease for which a drug is developed.