Synergistic interaction between valproate and lamotrigine against seizures induced by 4-aminopyridine and pentylenetetrazole in mice

We compared the effects of adding a non-protective dose of valproate to increasing doses of lamotrigine with those of monotherapy and vice versa in CD I mice. Anticonvulsant effects were evaluated against seizures induced by both 4-aminopyridine and pentylenetetrazole, and neurotoxic effects were evaluated by the rotarod test. Changes in anticonvulsants, gamma-aminobutyric acid (GABA) and glutamate concentrations in the whole brain were also assessed. Lamotrigine increased the potency ratio of valproate against 4-aminopyridine and pentylenetetrazole but not on rotarod, the protective index being increased from 1.1 to 2.4 against 4-aminopyridine and from 1.9 to 3.8 against pentylenetetrazole, without changes in brain valproate, and with a significant increase in brain GABA. Valproate increased the potency ratio of lamotrigine against 4-aminopyridine but not on rotarod, the protective index being increased from 4.4 to 7.3; valproate also increased brain lamotrigine (but only at low doses), brain GABA and brain glutamate. In conclusion, non-protective doses of lamotrigine increased the therapeutic index of valproate and vice versa, and these effects appeared to be pharmacodynamic. (C) 2002 Elsevier Science B.V. All rights reserved.