Chronic L-lysine develops anti-pentylenetetrazol tolerance and reduces synaptic GABAergic sensitivity

Abstract

L-Lysine 10 mmol/kg given to mice for 1 to 10 days significantly increased clonic and tonic seizure latencies caused by 60 mg/kg pentylenetetrazol (PTZ). On day 1 the clonic and tonic seizure latencies were increased from 160.4 ± 26.3 and 828.6 ± 230.8 s to 287.1 ± 103.3 and 982.3 ± 98.6 s, respectively. Both clonic and tonic seizure latencies increased steadily with additional L-lysine treatment without significant change in survival rate. On day 10, the anticonvulsant effect reached its highest level with a block of tonic seizures and a survival rate of 100% without tolerance developing. Acute L-lysine treatment significantly increased the mean clonic latency from 85.8 ± 5.24 to 128.2 ± 9.0 s and the mean tonic seizure latency from 287.2 ± 58.7 to 313.5 ± 42.2 s with 80 mg/kg PTZ. On the day 10 of treatment, the anticonvulsant effect of L-lysine was highest, with a significant increase of 155 and 184% in clonic and tonic latencies over the control, respectively. After 15- and 20-day treatment, clonic and tonic seizure latencies and survival rate decreased, suggesting development of tolerance. Brain membranes from tolerant mice showed decreased enhancement by γ-aminobutyric acid of specific [ 3H]flunitrazepam binding from 210 ± 8 to 169 ± 5% with EC 50 values of 4.1 ± 1.4 and 7.8 ± 1.5 μM, respectively. Scatchard analysis of [ 3H] flunitrazepam binding showed no significant change of apparent binding affinity (K D) or binding density (B max) after chronic L-lysine exposure. L-Lysine enhanced the specific [ 35S]tert-butyl bicyclophosphorothionate (TBPS) binding in brain membranes dose dependently. This enhancement was reduced from 38 to 10% in tolerant mouse brain membranes. The brain levels of L-lysine in the chronically L-lysine-treated mice did not vary significantly compared to those in animals before treatment.