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.