Long-lasting adaptations in the mesolimbic dopamine (DA) system in response to drugs of abuse likely mediate many of the behavioral changes that underlie addiction. Recent work suggests that long-term changes in synaptic strength at excitatory synapses in the two major components of this system, the nucleus accumbens (NAc) and ventral tegmental area, may be particularly important for the development of drug-induced sensitization, a process that may contribute to addiction, as well as for normal response-reinforcement learning. Using whole-cell patch-clamp recording techniques from in vitro slice preparations, we have examined the existence and basic mechanisms of long-term depression (LTD) at excitatory synapses on both GABAergic medium spiny neurons in the NAc and dopaminergic neurons in the midbrain. We find that both sets of synapses express LTD but that their basic triggering mechanisms differ. Furthermore, DA blocks the induction of LTD in the midbrain via activation of D2-like receptors but has minimal effects on LTD in the NAc. The existence of LTD in mesolimbic structures and its modulation by DA represent mechanisms that may contribute to the modifications of neural circuitry that mediate reward-related learning as well as the development of addiction.