MK-801 does not prevent acute stimulatory effects of amphetamine or cocaine on locomotor activity or extracellular dopamine levels in rat nucleus accumbens.

Recent work has shown that the development of behavioral sensitization to cocaine, amphetamine, and morphine is prevented by coadministration of N-methyl-D-aspartate (NMDA) antagonists such as MK-801. This suggests that NMDA receptors mediate long-term changes in neuronal responsiveness essential for the development of behavioral sensitization, similar to their role in other forms of neuronal plasticity. However, other studies, suggesting that NMDA receptor antagonists interfere with acute behavioral effects of psychomotor stimulants, call this interpretation into question and suggest that the ability of NMDA antagonists to prevent sensitization may reflect blockade of the acute effects of psychomotor stimulants. To examine this issue, behavioral and microdialysis studies assessed the effect of pretreatment with 0.1 mg/kg MK-801 on the ability of amphetamine and cocaine to stimulate locomotor activity and elevate extracellular dopamine (DA) levels in nucleus accumbens; this dose of MK-801 prevents sensitization when coadministered repeatedly with these stimulants. MK-801 pretreatment enhanced amphetamine-stimulated horizontal locomotion and stereotyped behavior. MK-801 pretreatment produced a modest attenuation of cocaine-stimulated horizontal locomotion, which may have reflected enhancement by MK-801 of certain components of cocaine-stimulated stereotypy. There was no effect of MK-801 pretreatment on the ability of amphetamine or cocaine to elevate extracellular DA levels in nucleus accumbens. These results suggest that the acute effects of cocaine and amphetamine on locomotor activity and extracellular DA levels are not prevented by MK-801, and that MK-801 must act through other mechanisms to prevent the development of behavioral sensitization.