Initial work on DA’s role in drug reward focused on the mesolimbic DA pathway—DA neurons in the ventral tegmental area (VTA) projecting into the NAc (1). More recent work now recognizes the crucial role of the mesostriatal (projections from substantia nigra into dorsal striatum) and mesocortical pathways (projections from the VTA into the frontal cortex) in drug reward and addiction (1). DA signals through five different receptors of which the most ubiquitous are the D1 (D1R) and D2 receptors (D2R), which are also the ones that are best understood. The low-affinity D1R is stimulated by large DA increases as induced by phasic DA cell firing and is implicated in drug reward and conditioning. The high-affinity D2R is stimulated by relatively low DA concentrations, as are induced by tonic DA cell firing, and it may interfere with drug reward (6). Differential adaptation in D1R versus D2R signaling pathways with repeated drug administration is likely to underlie neuroplastic changes in addiction. Overall in animal studies, the increases in D1R signaling are associated with sensitized responses to drugs, and the decreases in D2R
