SUMMARY The anticonvulsant sodium channel blocker lamotrigine (LTG) increases resting motor threshold (RMT) measured using transcranial magnetic stimulation (TMS) of the motor cortex in humans. However, studies suggest a weak relationship between LTG plasma concentration and increase in RMT. This undermines the possibility to use the technique to investigate the dose-efficacy relationship of lamotrigine or novel sodium channel blocking drugs. In order to investigate this relationship further, we have examined blood and brain concentrations of LTG in parallel with the drugs effects on RMT in a model in which electrical-stimulation is used to activate the motor cortex of propofol-anaesthetised rats. LTG (3-20 mg/kg s.c.) significantly increased RMT (P<0.001). There was a significant (P<0.01) positive correlation between LTG blood and brain concentration and increase in RMT; however correlation-coefficients were low (brain: r(2)=0.26 and blood r(2)=0.25), with evidence for non-responders, similar to human studies. The results show that the variation in RMT response is unlikely to be due to pharmacokinetic differences between subjects, and suggest that biological differences may underpin the variability. Understanding the source of this variability will be an important goal and, assuming some relationship between the effects of LTG on motor pathway excitability and the drugs anticonvulsant efficacy, could lead to a means to identify epilepsy patients that may be more likely to respond to treatment.