Anticonvulsant effects of the glycine/NMDA receptor ligands d‐cycloserine and d‐serine but not R‐(+)‐HA‐966 in amygdala‐kindled rats

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Abstract
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 μmol, significantly increased the ADT, while no effect was seen at a lower dose (2.5 μmol). 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.