Lamotrigine (LTG), 3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine, is a structurally novel anticonvulsant. The anticonvulsant profile of LTG following oral administration in two standard anticonvulsant tests, the maximal electroshock (MES) test in mice and rats and the pentylenetetrazol (PTZ) infusion test in mice, was studied in comparison with the known anticonvulsant drugs phenytoin (PHT), phenobarbitone, diazepam, carbamazepine (CBZ), sodium valproate, ethosuximide (ETH), and troxidone (TROX). ED50 values for the abolition of hindlimb extension (HLE) in the MES test and PTZ infusion tests and doses increasing the latency of PTZ-evoked clonus were determined. The duration of action of LTG was examined in rats and mice in the MES test by determining ED50 values for the abolition of HLE at various drug intervals to shock administration. In the MES test, LTG was well absorbed in both species, with peak activity at 1 h and persistence at this level of potency for at least 8 h. Of the drugs examined, LTG was ranked the most potent and persistent in both species. LTG also abolished PTZ-evoked HLE, while ETH and TROX were inactive. Clonus latency was not increased by LTG, PHT, or CBZ, but was significantly increased (p less than 0.05) by the remaining anticonvulsants. Thus, LTG resembled PHT and CBZ in its ability to block HLE but not to increase PTZ-induced clonus latency. Acute behavioural studies in mice and rats have suggested a wide separation between anticonvulsant doses and those producing behavioural impairment. These results suggest that LTG may be of value in the treatment of generalised tonic-clonic and partial seizures.

Lamotrigine (LTG), a new anticonvulsant, chemically unrelated to current antiepileptic drugs (AEDs), resembles phenytoin (PHT) and carbamazepine (CBZ) in ability to block hindlimb extension in both the maximal electroshock test and leptazol-induced seizures. Results indicate that LTG may be of value in both partial and generalized seizures. In in vitro studies, LTG has been shown to inhibit veratrine-evoked release of glutamate when a threshold depolarizing concentration (4 micrograms/ml) is used, and also inhibits aspartate release when a larger stimulus is given (10 micrograms/ml). However, LTG does not block potassium-evoked transmitter release. LTG is a less potent inhibitor of the release of gamma-aminobutyric acid (GABA), acetylcholine, noradrenaline, and dopamine. LTG blocks the neurotoxicity of kainic acid in vivo, supporting the in vitro findings, and suggests that the anticonvulsant effect of LTG may be due to inhibition of glutamate release. In a test of working memory and phencyclidine (PCP) discrimination studies, LTG had no effect, indicating no sharing of the same PCP-like side effects associated with NMDA receptor blockade. In the gerbil model of global ischemia, high doses of LTG provided protection against damage to the CA1 region of the hippocampus. Analogues of LTG of higher potency to block the release of glutamate may be necessary to ensure protection against ischemic brain damage.