The mechanisms underlying the systemic central nervous system (CNS) toxicity of lidocaine are still largely obscure and not solely explained by its classic action on Na+ channels. Here, we examined the hypothesis that Na+ channel-independent actions of lidocaine in the thalamus, a brain area previously implicated as a site for lidocaine’s systemic effects, contribute to its CNS toxicity. We investigated the effects of lidocaine at clinically CNS-toxic concentrations (100-600 μM) on firing properties of rat thalamocortical neurons in brain slices (250 μm) in vitro, using whole cell patch-clamp recording techniques. Brain slice preparations containing ventrobasal thalamic neurons were obtained from Wistar rats at postnatal days 13-16. Results are expressed as mean ± SEM and compared to control values by one-sample t tests, unless mentioned otherwise. Bath application of 100 μM lidocaine abolished typical tonic firing elicited in neurons current-clamped at -58 mV and evoked a distinct regular firing characterized by a more depolarized (higher) activation threshold (mean ± SD, -20.5 ± 8.4 mV vs. -44.3 ± 3 mV; n = 12; paired Student’s t test, P < 0.001) and a different spike configuration. The high-threshold (HT) potentials disappeared completely when superfusing medium was either deprived of Ca2+ or contained the high voltage-activated Ca2+ channel blocker Cd2+ (50 μM). The specific L-type Ca2+ channel blocker, nifedipine, at 5 μM, but not at 1 μM, completely blocked the HT potentials, whereas the N-type Ca2+ channel blocker, ω-conotoxin GVIA (1 μM) had little effect on them. Neurons pretreated with tetrodotoxin (TTX, 600 nM), a tonic blocker of voltage-gated Na+ channels, also exhibited regular firing of HT potentials. Their firing rate after reaching a maximum decreased in response to an increase in the magnitude of injected current due to the activation of a slowly recovering after-hyperpolarization (AHP) of the holding membrane potential. Application of lidocaine abolished the AHP and caused neurons to respond to an increase in the magnitude of injected current with increased rate of HT firing. Furthermore, lidocaine, at 600 μM, increased input resistance in TTX-pretreated neurons by 86 ± 9% (n = 4; P < 0.001) and reduced the magnitude of current pulses required to trigger HT potentials by 24 ± 7% (n = 4; P < 0.05). We conclude that lidocaine at clinically CNS-toxic concentrations unmasks Ca2+-dependent HT action potentials mediated by L-type Cav1.2 channels. Inhibition by lidocaine of the hyperpolarization-activated mixed cationic current, Ih, and K+ conductance(s) mediating slow AHPs(1), likely underlies its stronger unmasking effects compared to TTX. Overall, our findings support the notion that impaired Ca2+ homeostasis contributes to the complex and multifaceted mechanisms of supraspinal CNS toxicity of systemic lidocaine in vivo.