W. Loscher et al., ANTICONVULSANT EFFECTS OF THE GLYCINE NMDA RECEPTOR LIGANDS D-CYCLOSERINE AND D-SERINE BUT NOT R-(+)-HA-966 IN AMYGDALA-KINDLED RATS/, British Journal of Pharmacology, 112(1), 1994, pp. 97-106
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.