Lamotrigine has an anxiolytic-like profile in the rat conditioned emotional response test of anxiety: a potential role for sodium channels?

Rationale: Many anticonvulsants are used in disorders other than epilepsy. For example, lamotrigine is reported to be effective in post-traumatic stress disorder and mania. Objective: We assessed the effects of the anticonvulsants lamotrigine, valproate and carbamazepine in an animal model of anxiety. We assessed a wide range of pharmacological tools to delineate the mechanism of lamotrigine's anxiolytic effect. Methods: We assessed these compounds in the rat conditioned emotional response (CER) test of anxiety. Results: Lamotrigine (30-80 mg/kg) dose-dependently and reproducibly engendered an anxiolytic response in this test, with similar efficacy to benzodiazepines. Carbamazepine (20-40 mg/kg) and riluzole (10 mg/kg), which block Na+ channels by a similar mechanism as lamotrigine, were also anxiolytic. By contrast, valproate (100-600 mg/kg) was inactive and appears to differ in its interaction with Na+ channels. The SSRI paroxetine, the GABA(A) receptor positive modulator propofol, the NMDA antagonists memantine and (+) MK-801, and the Ca2+ channel antagonist nifedipine were all inactive in the CER test, suggesting these mechanisms may not mediate the anxiolytic effect of lamotrigine. More directly, we showed that the anxiolytic effect of lamotrigine could be blocked by co-administering rats with the Na+ channel activator veratrine (0.1 mg/kg). By contrast, neither the Ca2+ channel agonist BAYK8644 (0.5 mg/kg) nor the 5-HT1A or 5-HT1/2 antagonists WAY100635 (0.3 mg/kg) and metergoline (3 mg/kg), respectively, were able to block the effect. Conclusion: Lamotrigine's anxiolytic effect in the CER test may be mediated via block of Na+ channels, and this may represent a target for the development of novel anxiolytics.