Although cocaine and synthetic local anesthetics block nerve conductance by blockading Na+ current, toxic doses produce seizures both in rodents and humans. It has been generally accepted that local anesthetic-induced seizures are related to their inhibition of central inhibitory nervous systems, thereby stimulating excitatory neuronal activity. Cocaine has been shown to exert psychostimulant action by inhibiting the monoamine uptake system, while synthetic local anesthetics are believed to lack this effect. However, certain local anesthetics, including procaine, display cocaine-like psychostimulating effects in animals. Recently, an inhibitory action by certain local anesthetics on monoamine transporters (MAT) has been demonstrated, and this effect relates to their psychostimulating and seizure effects. Therefore, MAT play a critical role in regulating seizures and psychostimulation. This review summarizes the inhibitory action of local anesthetics on MAT, and the influences of acute and chronic pha rmacological manipulations of central nervous system functions on the central stimulating actions of local anesthetic and cocaine. The findings have important implications for safe and effective drug use and the development of new medicaments for treatment of cocaine abuse.