Anticonvulsant effects of the glycine/NMDA receptor ligands D-cycloserine and D-serine but not R-(+)-HA-966 in amygdala-kindled rats.
1. The effects of the glycine/NMDA receptor partial agonists, D-cycloserine and (+)-HA-966 and the full agonist, D-serine, on focal seizure threshold and behaviour have been determined in amygdala-kindled rats, i.e. a model of focal (partial) epilepsy. The uncompetitive NMDA receptor antagonist, MK-801, was used for comparison. 2. The high efficacy glycine partial agonist, D-cycloserine, did not alter the threshold for induction of amygdaloid afterdischarges (ADT) at doses of 20-80 mg kg-1 i.p., but significant ADT increases were determined after application of higher doses (160 and 320 mg kg-1). The ADT increases after these high doses were long-lasting; significant elevations were still observed 2 days after drug injection. Determination of D-cycloserine in plasma and brain tissue showed that it was rapidly eliminated from plasma. Compared to peak levels in plasma, only relatively low concentrations of D-cycloserine were measured in brain tissue. 3. The low efficacy glycine partial agonist, (+)-HA-966, 10-40 mg kg-1 i.p., did not alter the ADT or seizure recordings (seizure severity, seizure duration, afterdischarge duration) at ADT currents. However, the drug dose-dependently increased the duration of postictal behavioural and electroencephalographic depression in kindled rats. At the higher dose tested, postictal immobilization was dramatically increased from 3 min to about 120 min. This might indicate that glutamatergic activity is decreased postictally, which is potentiated or prolonged by (+)-HA-966. 4. Like D-cycloserine, the glycine receptor full agonist, D-serine, injected bilaterally into the lateral ventricles at a dose of 5 mumol, significantly increased the ADT, while no effect was seen at a lower dose (2.5 mumol). 5. The anticonvulsant effects observed with D-cycloserine were completely antagonized by combined treatment with (+)-HA-966, indicating that the effects of D-cycloserine were mediated by the glycine/NMDA receptor complex. 6. MK-801, 0.1 mg kg-1, did not alter the focal seizure threshold or seizure recordings at ADT current, but induced marked phencyclidine(PCP)-like behavioural alterations, such as hyperlocomotion, stereotypies and motor impairment. No PCP-like behaviours were observed after D-cycloserine, D-serine or (+)-HA-966. High doses of (+)-HA-966 induced moderate motor impairment in kindled rats. 7. The long lasting increases in seizure threshold observed after the high efficacy glycine partial agonist,D-cycloserine but not the low efficacy partial agonist, (+)-HA-966, may suggest that the effects of D-cycloserine are mediated by adaptive changes in the NMDA receptor complex in response to glycine receptor stimulation.8. Pharmacological intervention at the strychnine-insensitive glycine receptor by high-efficacy partial agonists with systemic bioavailability may be an effective means of increasing seizure-threshold without concomitantly inducing PCP-like adverse effects.
Department of Pharmacology, Toxicology, and Pharmacy, School of Veterinary Medicine, Hannover, Germany.
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Löscher
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Wlaź
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Rundfeldt
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Baran
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Hönack
D000679:Amygdala / Q000502:physiology*; D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D003523:Cycloserine / Q000037:antagonists & inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004558:Electric Stimulation; D017029:Epilepsy, Complex Partial / Q000188:drug therapy / Q000503:physiopathology; D005260:Female; D005998:Glycine / Q000494:pharmacology; D007696:Kindling, Neurologic / Q000502:physiology*; D011760:Pyrrolidinones / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D018009:Receptors, Glycine / Q000037:antagonists & inhibitors / Q000187:drug effects; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000187:drug effects; D012694:Serine / Q000494:pharmacology*
D000927:Anticonvulsants; D011760:Pyrrolidinones; D018009:Receptors, Glycine; D016194:Receptors, N-Methyl-D-Aspartate; D012694:Serine; D016291:Dizocilpine Maleate; D003523:Cycloserine; C001369:1-hydroxy-3-amino-2-pyrrolidone; D005998:Glycine