The role of N-methyl-D-aspartate (NMDA) receptors in specific D1 and D2 regulation of striatal and accumbens neurotensin (NT) systems was investigated. As demonstrated previously, stimulation of D1 receptors with multiple administrations of SKF 38393 significantly increased striatal and accumbens NT content to approximately 145% of control. These responses were completely blocked by coadministration of the non-competitive NMDA antagonist, MK 801. Previous studies have documented that D2 receptors tonically regulate striatal NT systems. Thus, multiple doses of sulpiride, a D2 antagonist, increased striatal NT content to 167% of control while quinpirole, a D2 agonist, decreased striatal NT content to 58% of control. MK 801 did not alter either striatal NT response to D2 manipulation. As previously reported, levels of accumbens NT changed only in response to D2 blockade and not to D2 stimulation. Thus, sulpiride increased accumbens NT content to 138% of control; this was not blocked by the coadministration of MK 801. NT content also significantly increased after stimulation of glutamate receptors with NMDA. To determine if D1 receptors participate in this NMDA-mediated change, the D1 antagonist SCH 23390 was coadministered. Blockade of D1 receptors did not significantly alter the response of striatal NT systems to NMDA. However, in both striatum and nucleus accumbens, the NMDA effect on NT systems appeared to be lessened. In summary, expression of D1-, but not D2-mediated changes in striatal and accumbens NT systems are markedly dependent on NMDA receptor activity. In comparison, expression of the NMDA-mediated changes in the same NT systems do not appear to be as dependent on D1 receptor activity.