The stimulation of cortical dopaminergic D1 receptors can counteract the increased locomotor activity evoked by D-amphetamine application in the nucleus accumbens (Vezina et al., Eur. J. Neurosci., 3, 1001–1007, 1991). Moreover, an α1 antagonist, prazosin, prevents the locomotor hyperactivity induced by electrolytic lesions of the ventral tegmental area (Trovero et al., Neuroscience, 47, 69–76, 1992). Attempts were thus made to see whether blockade of α1-adrenergic receptors in the rat prefrontal cortex could reduce nucleus accumbens D-amphetamine-evoked locomotor activity. Rats implanted chronically and bilaterally with cannulae into the medial prefrontal cortex and the nucleus accumbens were used for this purpose and locomotor activity was monitored in circular corridors. Preliminary experiments indicated that intraperitoneal injection of prazosin (0.06 mg/kg) reduces the locomotor hyperactivity induced by the peripheral administration of D-amphetamine (0.75 mg/kg). This effect of prazosin was not observed when locomotor hyperactivity was obtained by an intraperitoneal injection of scopolamine (0.8 mg/kg). Bilateral nucleus accumbens injections of D-amphetamine (4.0 nmol/side) markedly increased locomotor activity, as estimated in a 30 min period. Prior (20 min) bilateral injections of either prazosin or WB-4101 (0.16 pmol) into the medial prefrontal cortex abolished the nucleus accumbens D-amphetamine-evoked response. The recovery of the nucleus accumbens D-amphetamine-evoked response was closely dependent on the amount of prazosin used, very prolonged inhibitory effects of the drug being seen with a high amount (>4 days with 160 pmol). In contrast, whatever the amount of WB-4101 used (0.16–160 pmol), recovery occurred within 3 days. It is suggested that the blockade of cortical d-adrenergic receptors facilitates locally dopaminergic D1 transmission. This latter effect may counteract the increased locomotor activity induced by the application of D-amphetamine into the nucleus accumbens.