Abstracts

RATIONALE: Traditionally, the strychnine-sensitive glycine receptor (GlyR) was thought to only mediate inhibitory neurotransmission in the spinal cord and brainstem. GlyR, however, was recently found in the mammalian cortex where its activation is inhibitory. Since strychnine induces seizures, potentiating GlyR function may contribute to the action of known antiepileptic drugs (AED). Indeed, AED with multiple mechanisms of action may be preferred. Therefore, we tested the hypothesis that clinically relevant concentrations of six AED (carbamazepine, felbamate, gabapentin, pentobarbital, phenytoin, valproate) potentiate GlyR.
METHODS: GlyR-mediated currents were evoked in cultured embryonic mouse hippocampal neurons, voltage-clamped at -60mV, using the whole-cell patch clamp technique. All drugs were applied using a multibarrel flow tube perfusion system. For each neuron, we measured peak currents induced by 50[mu]M glycine (EC50) in the presence and absence of various concentrations of each AED. 2-8 neurons were used for each agent at each concentration. Data are presented as mean [plusminus] standard error of the mean.
RESULTS: 1. None of the AED alone elicited a current at the concentrations used except for pentobarbital.
2. At or below clinically relevant concentrations, carbamazepine, felbamate, phenytoin and valproate had no effect on glycine currents. Higher concentrations inhibited glycine currents (table). The inhibition by valproate was greater at +30mV.
3. Gabapentin had no effect at any of the concentrations tested (5, 50, 500[mu]M).
4. Pentobarbital at concentrations of 0.1, 1, and 10[mu]M had no effect on glycine currents. 100[mu]M pentobarbital induced its own inward current and inhibited glycine currents by 20 [plusminus] 8%.
CONCLUSIONS: These results indicate that GlyR modulation does not play a significant role in the mechanism of action of the antiepileptic agents tested.[table]
Support: National Institute of Health