Chronic morphine administration (via subcutaneous pellet) decreases the size of dopamine neurons in the ventral tegmental area (VTA), a key reward region in the brain, yet the molecular basis and functional consequences of this effect are unknown. In this study, we used viral-mediated gene transfer in rat to show that chronic morphine-induced downregulation of the insulin receptor substrate 2 (IRS2)-thymoma viral proto-oncogene (Akt) signaling pathway in the VTA mediates the decrease in dopamine cell size seen after morphine exposure and that this downregulation diminishes morphine reward, as measured by conditioned place preference. We further show that the reduction in size of VTA dopamine neurons persists up to 2 weeks after morphine withdrawal, which parallels the tolerance to morphine’s rewarding effects caused by previous chronic morphine exposure. These findings directly implicate the IRS2-Akt signaling pathway as a critical regulator of dopamine cell morphology and opiate reward. (emphasis supplied)