The influence of strychnine-insensitive glycine receptor agonists and antagonists on generalized seizure thresholds.
We have examined the influence of strychnine-insensitive glycine (gly2) receptor agonists and antagonists on the expression of generalized seizure activity (generalized seizure threshold (GST), afterdischarge duration and motor seizure response) in fully amygdala kindled rats. Intra-amygdaloid administration of the selective gly2 receptor antagonist, 7-chlorokynurenic acid (7-C1KYN) (10-50 nmol) dose-dependently raised GSTs in a glycine-reversible manner. The same doses had no significant effect on other parameters of seizure expression. (+/-)-3-Amino-1-hydroxy-2-pyrrolidone (HA-966), a proposed low-efficacy partial agonist at the gly2 receptor17, showed similar but weaker anticonvulsant activity in this model. The active, R-(+)-enantiomer of HA-966 showed greater anticonvulsant efficacy than the racemic mixture, but was still clearly less active than 7-C1KYN. The gly2 receptor agonists glycine (10-50 nmol), D-serine (50 nmol) and D-alanine (50 nmol) failed to influence any of the parameters of the seizure response, suggesting that gly2 receptors in the basolateral amygdala are fully saturated in vivo. The behavioural impairment induced by high doses of 7-C1KYN did not appear to be associated with gly2 receptor blockade. These results support the concept that potent and selective gly2 receptor antagonists may provide a useful, novel class of anticonvulsant agents.
Croucher
M J
MJ
Department of Biochemistry, Imperial College of Science, Technology and Medicine, London, U.K.
Bradford
H F
HF
D000409:Alanine / Q000494:pharmacology*; D000679:Amygdala / Q000187:drug effects / Q000502:physiology* / Q000503:physiopathology; D000818:Animals; D005998:Glycine / Q000494:pharmacology*; D007696:Kindling, Neurologic; D007736:Kynurenic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D008297:Male; D011760:Pyrrolidinones / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D018009:Receptors, Glycine; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D017981:Receptors, Neurotransmitter / Q000187:drug effects / Q000502:physiology*; D012640:Seizures / Q000503:physiopathology*; D012694:Serine / Q000494:pharmacology*; D013331:Strychnine / Q000494:pharmacology*
D011760:Pyrrolidinones; D018009:Receptors, Glycine; D016194:Receptors, N-Methyl-D-Aspartate; D017981:Receptors, Neurotransmitter; D012694:Serine; C001369:1-hydroxy-3-amino-2-pyrrolidone; D007736:Kynurenic Acid; D013331:Strychnine; D000409:Alanine; C057013:7-chlorokynurenic acid; D005998:Glycine