Abstract Since the medial prefrontal cortex receives converging projections from the mediodorsal nucleus of the thalamus (MD) and the dopaminergic neurons located in the ventromedial mesencephalic tegmentum (VMT) the responses of cortical neurons to ipsilateral VMT and MD stimulation (50–150 μA; 0.2–0.5 ms duration) were analyzed in ketamine anaesthetized rats. MD stimulation at 1 Hz blocked the firing of 90% of the spontaneously active cortical units tested (mean latency, 15 ms; mean duration, 182 ms). MD stimulation at 5–10Hz evoked single spike responses (mean latency, 16 ms) in 80% of the units tested. Ten to 15 days after kainic acid injection into the MD the number of cortical neurons inhibited (1 Hz) or excitated (5–10 Hz) was reduced to 57 and 18%, respectively. Following stimulation of the VMT (at a frequency of 1–5 Hz), 85% of cortical neurons showed an arrest of spontaneous firing occurring after a mean latency of 17 ms and lasting 109 ms on the average. Most of the cells displaying the VMT inhibitory effect were excitated by MD stimulation. Moreover VMT stimulation, applied 3–45 ms before that of MD, blocked the excitation induced by MD in 75% of the units tested. After injection of 6-hydroxydopamine into the medial forebrain bundle or intraperitoneal administration of α-methyl-paratyrosine (α-MpT), the number of units tested responding to VMT stimulation was of 19 and 35%, respectively. Moreover in these treated rats, the proportion of excitatory responses to MD blocked by VMT stimulation was reduced to 5 and 6%. On the other hand, the effects induced by VMT stimulation were not affected after specific destruction of the noradrenergic ascending system. These results suggest that the mesocortical dopaminergic neurons modulate the influence of the main thalamic afferent on the prefrontal cortical cells.