Cerebral monoamines and lidocaine toxicity in rats

The effect of alterations in whole brain monoamine content on the plasma lidocaine concentration resulting in seizures was studied in rats. Reductions in brain monoamine content were produced by treatment with one of the following drugs: reserpine, parachlorophenylalanine (PCPA), or alpha methyl paratyrosine (AMPT). Reserpine depleted norepinephrine (NE), and dopamine (DA) by 75 per cent and serotonin (5HT) by 54 per cent; PCPA reduced brain 5HT 56 per cent without changing NE and DA; AMPT reduced brain NE and DA by 54 and 60 per cent, respectively, without altering 5HT content. Treatment with 5-hydroxytryptophan, a serotonin precursor combined with the peripheral decarboxylase inhibitor RO4-4602 increased brain 5HT content by 400 per cent without changes in DA and NE. Whole brain NE concentrations were assayed fluorometrically, DA brain concentrations were assayed by HPLC, and lidocaine concentrations in plasma were determined by gas chromatography. Plasma lidocaine concentrations at the onset of convulsions were found to be elevated significantly only by drugs causing serotonin depletion; increasing to 128 per cent of control with reserpine treatment and 139 per cent of control with PCPA treatment. Depletion of NE and DA had no effect on the lidocaine seizure threshold. Increases in brain 5HT caused a small but not statistically significant decrease to 94 per cent of control in the mean plasma lidocaine concentration at seizure onset.