The induction of behavioral sensitization to D-amphetamine (AMPH) is known to result at least in part from an action of the drug in the ventral tegmental area (VTA), which contains the dopamine (DA) A10 cell bodies. To specify the cellular mechanisms through which AMPH acts in the VTA and leads to behavioral sensitization after repeated intra-VTA injections, the involvement of VTA DA D1 and D2 and serotonin2 receptors in this phenomenon was investigated in independent experiments. The results reported here confirm that repeated intra-VTA AMPH injections (four injections of 5 micrograms/0.5 microliter every other day) induce behavioral sensitization, as revealed by the potentiation of the locomotor response to peripheral challenges with AMPH (0.5 mg/kg) 4 or 15 days after treatment. This behavioral sensitization induced by intra-VTA administration of AMPH cross-reacts with morphine (1 microgram/0.5 microliter) administered into the VTA 7 days after treatment. We demonstrated that the D1 receptor antagonist (R)-(+)-8-chloro-2,3,4, 5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepin-7-ol (0, 0.01, 0.1 and 1 microgram/ 0.5 microliter) coadministered in the VTA with AMPH dose-dependently prevents the behavioral sensitization to peripheral AMPH challenges (at either 4 or 15 days after treatment) as well as the cross-sensitization with intra-VTA morphine. Neither DA D2 nor serotonin2 receptor blockade, using sulpiride (10 micrograms/0.5 microliters) and ketanserin (1 micrograms/0.5 microliters), respectively, had any effect on the induction of behavioral sensitization. In conclusion, these results demonstrate the selective involvement of VTA DA D1 receptors in the process by which AMPH acts in the VTA to induce behavioral sensitization.