L-LYSINE IS A BARBITURATE-LIKE ANTICONVULSANT AND MODULATOR OF THE BENZODIAZEPINE RECEPTOR

Our earlier observations showed that L-lysine enhanced the activity of diazepam against seizures induced by pentylenetetrazol (PTZ), and increased the affinity of benzodiazepine receptor binding in a manner additive to that caused by gamma-aminobutyric acid (GABA). The present paper provides additional evidence to show that L-lysine has central nervous system depressant-like characteristics. L-lysine enhanced [H-3]flunitrazepam(FTZ) binding in brain membranes was dose-dependent and stimulated by chloride, bromide and iodide, but not fluoride. Enhancement of [H-3]FTZ binding by L-lysine at a fixed concentration was increased by GABA but inhibited by pentobarbital between 10(-7) to 10(-3)M. While GABA enhancement of [H-3]FTZ binding was inhibited by the GABA mimetics imidazole acetic acid and tetrahydroisoxazol pyridinol, the enhancement by pentobarbital and L-lysine of [H-3]FTZ binding was dose-dependently increased by these two GABA mimetics. The above results suggest that L-lysine and pentobarbital acted at the same site of the GABA/benzodiazepine receptor complex which was different from the GABA binding site. The benzodiazepine receptor antagonist imidazodiazepine Ro15-1788 blocked the antiseizure activity of diazepam against PTZ. Similar to pentobarbital, the anti-PTZ effect of L-lysine was not blocked by Ro15-1788. Picrotoxinin and the GABA, receptor antagonist bicuculline partially inhibited L-lysine's enhancement of [H-3]FTZ binding with the IC(50)s of 2 mu M and 0.1 mu M, respectively. The convulsant benzodiazepine Ro5-3663 dose-dependently inhibited the enhancement of [H-3]FTZ binding by L-lysine. This article shows the basic amino acid L-lysine to have a central nervous system depressant characteristics with an anti-PTZ seizure activity and an enhancement of [H-3]FTZ binding similar to that of barbiturates but different from GABA.