1. In extensively washed synaptic membrane preparations from rat prefrontal cortex, the "in vitro" addition of either the D1 (SKF 38393) or the D2 (LY 171555) specific agonists markedly decreased the apparent affinity of the NMDA receptor antagonist [3H]-MK801 specific binding. In the same membrane preparation, the concentration of L-glutamate required to produce half maximal enhancement of [3H]-MK801 binding was approximately the same both in the presence or in the absence of dopaminergic drugs. 2. I.c.v. administration of the neurotoxin 6-OHDA resulted in a dramatic reduction of dopamine (DA) prefrontal cortex levels, whilst repeated administrations (21 consecutive days) with either the D1 (SCH 23390) or the D2 (YM 09151-2) selective antagonist failed to change DA and DOPAC contents. 3. Repeated administrations with the D1 receptor blocker SCH 23390 selectively increased the Bmax values of [3H]-SCH 23390 binding while [3H]-spiroperidol binding was increased both by repeated administrations of YM 09151-2 and by i.c.v. injection of 6-OHDA. 4. Although both chronic D2 blockade and 6-OHDA lesions consistently increased D2 receptor number, in extensively washed synaptic plasma membranes (SPM) of rats repeatedly administered with YM 09151-2 but not with 6-OHDA, the [3H]-MK801 binding was increased. 5. It is concluded that the effects of NMDA receptor activation could not be directly mediated by stimulation of DA release, but are highly dependent upon the presence of DA axon terminals.