MK-801, a non-competitive antagonist at the N-methyl-D-aspartate (NMDA) subtype of central glutamate receptor, stimulates locomotor activity in rats. Administration of MK-801 (0.25mg/kg, i.p.) on four consecutive days results in progressive sensitization of its locomotor stimulatory effects. Because of the importance of dopamine (DA) systems in locomotor sensitization to other stimulants (e.g. amphetamine and cocaine), we examined the possible role of DA transmission in MK-801 sensitization. The D1 antagonist SCH 23390 was used for these experiments because of the well-established ability of D1 antagonists to block both D1- and D2-mediated unconditioned behaviors. Acute behavioral effects of MK-801 were reduced by SCH 23390 only at doses that decreased basal activity, while the expression of MK-801 sensitization was attenuated by SCH 23390 in some experiments but never completely prevented. Co-administration of SCH 23390 with MK-801 on pretreatment days did not prevent the development of sensitization. In vivo microdialysis experiments compared the effect of MK-801 on extracellular DA levels in the nucleus accumbens (NAc) on Days 1 and 4 of repeated administration. On Day 1, MK-801 produced a modest elevation of DA levels. On Day 4, only 6/17 rats in microdialysis experiments expressed sensitization; these rats, however, exhibited a more rapid rise in DA levels than Day 1 rats or non-sensitized Day 4 rats. Electrophysiological studies revealed that repeated MK-801 administration resulted in supersensitivity of D1 receptors on NAc neurons. Thus, behavioral studies support the importance of non-dopaminergic mechanisms in MK-801 sensitization, while neurochemical and electrophysiological studies suggest that MK-801 sensitization is accompanied by changes in DA transmission in the NAc similar to those observed in amphetamine- or cocaine-sensitized rats.