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-cyclose rine and (+)-HA-966 and the full agonist, D-serine, on focal seizure t hreshold and behaviour have been determined in amygdala-kindled rats, i.e. a model of focal (partial) epilepsy. The uncompetitive NMDA recep tor antagonist, MK-801, was used for comparison. 2 The high efficacy g lycine 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 applica tion 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 i n plasma and brain tissue showed that it was rapidly eliminated from p lasma. Compared to peak levels in plasma, only relatively low concentr ations of D-cycloserine were measured in brain tissue. 3 The low effic acy glycine partial agonist, (+)-HA-966, 10-40 mg kg(-1) i.p., did not alter the ADT or seizure recordings (seizure severity, seizure durati on, afterdischarge duration) at ADT currents. However, the drug dose-d ependently increased the duration of postictal behavioural and electro encephalographic depression in kindled rats. At the higher dose tested , postictal immobilization was dramatically increased from 3 min to ab out 120 min. This might indicate that glutamatergic activity is decrea sed postictally, which is potentiated or prolonged by (+)-HA-966. 4 Li ke D-cycloserine, the glycine receptor full agonist, D-serine, injecte d bilaterally into the lateral ventricles at a dose of 5 mu mol, signi ficantly increased the ADT, while no effect was seen at a lower dose ( 2.5 mu mol). 5 The anticonvulsant effects observed with D-cycloserine were completely antagonized by combined treatment with (+)-HA-966, ind icating 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 foc al seizure threshold or seizure recordings at ADT current, but induced marked phencyclidine(PCP)-like behavioural alterations, such as hyper locomotion, 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 ef ficacy glycine partial agonist, D-cycloserine but not the low efficacy partial agonist, (+)-HA-966, may suggest that the effects of D-cyclos erine are mediated by adaptive changes in the NMDA receptor complex in response to glycine receptor stimulation, 8 Pharmacological intervent ion at the strychnine-insensitive glycine receptor by high-efficacy pa rtial agonists with systemic bioavailability may be an effective means of increasing seizure threshold without concomitantly inducing PCP-li ke adverse effects.