The sensorimotor cortex (SMCx) sends numerous projections to the striatum. These projections are excitatory and glutamate mediated. Glutamatergic receptors, specifically those of NMDA type-receptors, are closely related to excitotoxicity. Thus, in some circumstances, an excess of Ca2+ influx through NMDA channels alters neuronal metabolism and may become lethal for the cell. Two other divalent cations, Mg2+ and Zn2+, have inhibitory effects on NMDA receptors. Magnesium ions exert a voltage-dependent block of the NMDA calcium channel, whereas zinc ions exert a voltage-independent NMDA block. In the present work, the effects of iontophoresis of Mg2+ and Zn2+ on the striatal response to SMCx stimulation were studied. Moreover melatonin, an indoleamine with anticonvulsant properties and inhibitory effects on the NMDA receptor, was also iontophorized alone or in combination with Mg2+ and Zn2+. Single pulse electrical stimulation of SMCx produced an excitatory response in the striatum. Iontophoresis of melatonin, Mg2+ and Zn2+ produced a potent attenuation of the excitatory response of the striatum to SMCx stimulation, although the latency of the effect of melatonin was longer than those of Mg2+ and Zn2+. When these cations were simultaneously ejected with melatonin, additive inhibitory effects were recorded. These observations suggest that the inhibitory effects produced by Mg2+ and Zn2+ and melatonin are produced via different processes, and thus the inhibitory role of melatonin on the NMDA receptor activity is exclusive of a direct action on the NMDA calcium channel.